LIBRARY 

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CALIFORNIA 
SANTA   CRUZ 


YALE  UNIVERSITY 

MRS.  HEPSA  ELY  SILLIMAN  MEMORIAL 
LECTURES 


RESPIRATION 


SILLIMAN   MEMORIAL   LECTURES 

PUBLISHED  BY  YALE  UNIVERSITY  PRESS 


ELECTRICITY  AND  MATTER.  By  JOSEPH  JOHN  THOMSON,  D.SC.,  LL.D.,  PH.D., 
F.R.S.  Fellow  of  Trinity  College  and  Cavendish  Professor  of  Experimental 
Physics,  Cambridge  University.  {Fourth  printing.} 

THE  INTEGRATIVE  ACTION  OF  THE  NERVOUS  SYSTEM.  By  CHARLES 
S.  SHERRINGTON,  D.SC.,  M.D.,  HON.  LL.D.  TOR.,  F.R.S.,  Holt  Professor  of  Physi- 
ology, University  of  Liverpool.  {Sixth  printing.} 

RADIOACTIVE  TRANSFORMATIONS.  By  ERNEST  RUTHERFORD,  D.SC.,  LL.D., 
F.R.S.,  Macdonald  Professor  of  Physics,  McGill  University.  {Second  printing.} 

EXPERIMENTAL  AND  THEORETICAL  APPLICATIONS  OF  THERMO- 
DYNAMICS TO  CHEMISTRY.  By  DR.  WALTER  NERNST,  Professor  and 
Director  of  the  Institute  of  Physical  Chemistry  in  the  University  of  Berlin. 

PROBLEMS  OF  GENETICS.  By  WILLIAM  BATESON,  M.A.,  F.R.S.,  Director  of 
the  John  Innes  Horticultural  Institution,  Merton  Park,  Surrey,  England.  {Sec- 
ond printing.} 

STELLAR  MOTIONS.  With  Special  Reference  to  Motions  Determined  by  Means 
of  the  Spectrograph.  By  WILLIAM  WALLACE  CAMPBELL,  SC.D.,  LL.D.,  Director  of 
the  Lick  Observatory,  University  of  California.  {Second  printing.} 

THEORIES  OF  SOLUTIONS.  By  SVANTE  ARRHENIUS,  PH.D.,  SC.D.,  M.D.,  Di- 
rector of  the  Physico-Chemical  Department  of  the  Nobel  Institute,  Stockholm, 
Sweden.  {Third  printing.} 

IRRITABILITY.  A  Physiological  Analysis  of  the  General  Effect  of  Stimuli  in 
Living  Substances.  By  MAX  VERWORN,  M.D.,  PH.D.,  Professor  at  Bonn  Physio- 
logical Institute.  {Second  printing.} 

PROBLEMS  OF  AMERICAN  GEOLOGY.  By  WILLIAM  NORTH  RICE,  FRANK 
D.  ADAMS,  ARTHUR  P.  COLEMAN,  CHARLES  D.  WALCOTT,  WALDEMAR  LIND- 
GREN,  FREDERICK  LESLIE  RANSOME,  AND  WILLIAM  D.  MATTHEW.  {Second 
printing. } 

THE  PROBLEM  OF  VOLCANISM.  By  JOSEPH  PAXSON  IDDINGS,  PH.B.,  SC.D. 
{Second  printing.} 

ORGANISM  AND  ENVIRONMENT  AS  ILLUSTRATED  BY  THE  PHYSI- 
OLOGY OF  BREATHING.  By  JOHN  SCOTT  HALDANE,  M.D.,  LL.D.,  F.R.S., 

Fellow  of  New  College,  Oxford  University.   {Second  printing.} 

A  CENTURY  OF  SCIENCE  IN  AMERICA.  With  Special  Reference  to  the 
American  Journal  of  Science  1818-1918.  By  EDWARD  SALISBURY  DANA, 
CHARLES  SCHUCHERT,  HERBERT  E.  GREGORY,  JOSEPH  BARRELL,  GEORGE  OTIS 
SMITH,  RICHARD  SWANN  LULL,  Louis  V.  PIRSSON,  WILLIAM  E.  FORD,  R.  B. 
SOSMAN,  HORACE  L.  WELLS,  HARRY  W.  FOOTE,  LEIGH  PAGE,  WESLEY  R.  COE, 
AND  GEORGE  L.  GOODALE. 

THE   EVOLUTION  OF   MODERN   MEDICINE.   By  the  late   SIR  WILLIAM 

OSLER,   BART.,   M.D.,   F.R.S. 

RESPIRATION.  By  J.  S.  HALDANE,  M.D.,  LL.D.,  F.R.S.,  Fellow  of  New  College, 
Oxford,  H on.  Professor,  Birmingham  University. 


RESPIRATION 


BY 


J.  S.  HALDANE 

M.D.,  LL.D.,  F.R.S. 

FELLOW  OF  NEW  COLLEGE,  OXFORD 
HON.  PROFESSOR,  BIRMINGHAM  UNIVERSITY 


NEW  HAVEN 
YALE  UNIVERSITY  PRESS 

LONDON  :  HUMPHREY  MILFORD  :  OXFORD  UNIVERSITY  PRESS 
MDCCCCXXVII 


COPYRIGHT  1922  BY  YALE  UNIVERSITY  PRESS 
PRINTED  IN  THE  UNITED  STATES  OF  AMERICA 


First  published,  May,  1922. 
Second  printing,  January,   1927. 


THE  SILLIMAN  FOUNDATION 

IN  the  year  1883  a  legacy  of  eighty  thousand  dollars  was  left  to  the 
President  and  Fellows  of  Yale  College  in  the  city  of  New  Haven,  to  be 
held  in  trust,  as  a  gift  from  her  children,  in  memory  of  their  beloved  and 
honored  mother,  Mrs.  Hepsa  Ely  Silliman. 

On  this  foundation  Yale  College  was  requested  and  directed  to  estab- 
lish an  annual  course  of  lectures  designed  to  illustrate  the  presence  and 
providence,  the  wisdom  and  goodness  of  God,  as  manifested  in  the 
natural  and  moral  world.  These  were  to  be  designated  as  the  Mrs.  Hepsa 
Ely  Silliman  Memorial  Lectures.  Tt  was  the  belief  of  the  testator  that 
any  orderly  presentation  of  the  facts  of  nature  or  history  contributed  to 
the  end  of  this  foundation  more  effectively  than  any  attempt  to  empha- 
size the  elements  of  doctrine  or  of  creed ;  and  he  therefore  provided  that 
lectures  on  dogmatic  or  polemical  theology  should  be  excluded  from  the 
scope  of  this  foundation,  and  that  the  subjects  should  be  selected  rather 
from  the  domains  of  natural  science  and  history,  giving  special  promi- 
nence to  astronomy,  chemistry,  geology,  and  anatomy. 

It  was  further  directed  that  each  annual  course  should  be  made  the 
basis  of  a  volume  to  form  part  of  a  series  constituting  a  memorial  to 
Mrs.  Silliman.  The  memorial  fund  came  into  the  possession  of  the  Cor- 
poration of  Yale  University  in  the  year  1901 ;  and  the  present  volume 
constitutes  the  fourteenth  of  the  series  of  memorial  lectures. 


PREFACE 

WHEN  Yale  University  invited  me  to  deliver  the  Silliman  Lectures 
for  1915  I  was  asked  to  deal  with  the  physiology  of  breathing 
and  include  a  general  account  of  the  long  series  of  investigations 
with  which  I  had  been  associated  on  this  subject  and  its  practical 
applications  in  clinical  medicine  and  hygiene.  Owing  to  the  war  I 
was  unable  to  give  the  lectures  in  1915,  but  in  1916  delivered  four 
lectures  which  dealt  only  with  some  of  the  more  general  conclu- 
sions to  which  I  had  been  led,  and  were  published  early  in  1917 
by  the  Yale  University  Press  under  the  title  ''Organism  and 
Environment  as  Illustrated  by  the  Physiology  of  Breathing." 

The  war  has  greatly  delayed  the  appearance  of  the  present 
book,  which  treats  the  physiology  of  breathing  fully  in  accordance 
with  the  original  plan.  I  have,  however,  abandoned  the  lecture 
form,  and  what  I  had  written  four  years  ago  has  had  to  be  largely 
recast  owing  to  the  rapid  advance  of  knowledge.  The  book  is  not 
a  mere  compilation,  but  contains  much  that  has  never  previously 
been  published,  and  is  an  attempt  to  give  a  coherent  statement 
and  interpretation  of  what  is  known  of  the  subject  at  present.  1 
fear  that  I  may  sometimes  have  unwittingly  overlooked  observa- 
tions by  others  which  would  have  added  completeness  to  my 
account.  Yet  I  hope  that  what  may  have  been  lost  in  this  way 
will  be  made  up  for  by  the  fact  that  the  book  embodies  the  results 
of  a  continuous  series  of  investigations  leading  to  very  definite 
and  consistent  conclusions. 

About  the  middle  of  last  century  the  younger  physiologists 
broke  away  from  the  vitalistic  traditions  which  had  been  handed 
down  to  them,  and  set  about  to  investigate  living  organisms 
piece  by  piece,  precisely  as  they  would  investigate  the  working 
of  a  complex  mechanism.  This  method  seemed  to  them  to  promise 
success,  and  was  popularized  by  such  masters  of  clear  and  force- 
ful expression  as  Huxley.  It  is  still  the  orthodox  method  of  physi- 
ology, but  the  old  confidence  in  it  has  steadily  diminished  in 
proportion  as  exact  experimental  investigation  has  shown  that  the 
various  activities  of  a  living  organism  cannot  be  interpreted  in 
isolation  from  one  another,  since  organic  regulation  dominates 
them.  The  keynote  of  this  book  is  the  organic  regulation  of 
breathing  and  its  associated  phenomena. 


viii  RESPIRATION 

The  mechanistic  theory  of  life  is  now  outworn  and  must  soon 
take  its  place  in  history  as  a  passing  phase  in  the  development^  of 
biology.  But  physiology  will  not  go  back  to  the  vitalism  which 
was  threatening  to  strangle  it,  and  from  which  it  escaped  last 
century.  The  real  lesson  of  the  movement  of  that  time  will  never 
be  lost. 

The  book  belongs  to  a  transition  period,  but  the  transition  is 
forward  and  not  backward.  My  treatment  of  the  subject  may 
possibly  be  looked  on  askance  in  some  quarters  as  reactionary: 
for  I  have  been  largely  influenced  by  the  ideas  and  work  of  older 
physiologists.  If,  however,  I  have  gone  backward,  it  is  only  to 
pick  up  clues  which  had  been  temporarily  lost;  and  all  of  these 
clues  lead  forward — forward  to  a  new  physiology  which  embodies 
what  was  really  implicit  in  the  old. 

The  leaders  of  the  mechanistic  movement  of  last  century  got 
rid  of  vitalism,  but  in  doing  so  got  rid  of  life  itself.  I  have  tried 
to  paint  a  picture  of  the  body  as  alive.  Though  the  picture  is 
imperfect,  others  will  soon  paint  it  more  completely.  The  time 
has  come  for  a  far  more  clear  realization  of  what  life  implies. 
The  bondage  of  biology  to  the  physical  sciences  has  lasted  more 
than  half  a  century.  It  is  now  time  for  biology  to  take  her  rightful 
place  as  an  exact  independent  science :  to  speak  her  own  language, 
and  not  that  of  other  sciences. 

The  endeavor  to  represent  the  facts  of  physiology  as  if  they 
would  fit  into  the  general  scheme  of  a  mechanistic  biology  has 
led,  it  seems  to  me,  to  the  present  estrangement  between  physiology 
and  medicine.  Since  the  time  of  Hippocrates  the  growth  of 
scientific  medicine  has  in  reality  been  based  on  the  study  of  the 
manner  in  which  what  he  called  the  "nature"  (  <£iW  )  of  the 
living  body  expresses  itself  in  response  to  changes  in  environ- 
ment, and  reasserts  itself  in  face  of  disturbance  and  injury.  The 
underlying  assumption  is  that  organic  regulation  and  maintenance 
represent  something  very  real,  and  that  only  through  the  study 
of  it  can  we  recognize  and  interpret  disturbance  of  health,  and 
effectively  aid  maintenance  or  restoration  of  health.  I  have  en- 
deavored to  return  to  what  seems  to  me  the  truly  scientific  Greek 
tradition,  and  to  give  it  a  form  which  is  not  only  consistent  with 
modern  science  and  philosophy,  but  brings  physiology  and  medi- 
cine into  that  close  and  special  relation  indicated  by  the  common 
etymology  of  the  words  "physician"  and  "physiology." 

Most  of  the  investigations  specially  referred  to  in  the  book 
have  been  carried  out  on  man.  It  was  only  by  human  experiments 


RESPIRATION  ix 

that  the  almost  incredible  delicacy  of  the  regulation  of  breathing 
was  discovered;  and  human  experiments  have  revealed  to  us  in 
other  ways  how  rough  many  of  the  experiments  on  animals,  or 
on  "preparations"  from  the  bodies  of  animals,  have  been.  Organic 
regulation,  with  its  all-important  relations  to  practical  medicine 
and  surgery,  was  often  entirely  overlooked.  I  hope  that  the  book 
may  contribute  towards  establishing  human  physiology  in  its 
rightful  place,  which  has  been  usurped  too  long  by  experiments 
on  fragments  of  frogs  and  other  animals,  or  on  the  mere  super- 
ficial physical  and  chemical  aspects  of  bodily  activity. 

I  wish  to  offer  my  sincere  thanks  to  Yale  University  for  the 
honor  it  has  done  me  in  inviting  me  to  give  the  Silliman  Lectures. 
Between  Oxford  and  Yale  Universities  there  is  a  traditional 
association,  and  to  me  in  particular  the  association  stands  for 
friendship,  hospitality,  and  community  of  ideas.  My  only  regret 
is  that  in  coming  to  Yale  to  lecture  on  the  physiology  of  breathing 
I  seemed  to  be  doing  what  an  Englishman  calls  bringing  coals 
to  Newcastle,  since  I  had  to  refer  so  frequently  to  the  results 
reached  at  Yale  by  Professor  Yandell  Henderson  and  his  pupils. 

The  book  sums  up  the  results  of  more  than  twenty  years  of  my 
own  experimental  work,  thought,  reading,  and  discussion.  To  the 
old  pupils  and  other  friends  who  have  worked  and  thought  with 
me,  including  friends  in  the  mining  and  engineering  professions 
and  in  the  Navy  and  Army,  I  wish  to  express  my  debt.  Their 
names  are  often  quoted  in  the  text,  but  I  should  like  to  say  how 
much  I  have  been  aided  more  particularly  by  Professor  Lorrain 
Smith,  Professor  Pembrey,  Professor  Boycott,  Commander  Da- 
mant,  Mr.  Mavrogardato,  Dr.  Priestley,  Dr.  Douglas,  Professor 
Meakins,  and  my  son.  In  connection  with  the  Pike's  Peak  Scien- 
tific Expedition,  the  results  of  which  occupy  such  a  prominent 
place  in  the  book,  Dr.  Douglas  and  I  had  the  great  advantage 
of  being  associated  with  Professor  Yandell  Henderson  and  another 
Yale  graduate,  Professor  Schneider  of  Colorado  Springs.  The 
book  owes  much  to  the  talks  we  had  on  the  Peak  in  the  summer 
evenings  when  our  work  was  over  and  the  lights  were  twinkling 
over  the  prairie  far  below  from  Denver  to  Pueblo. 

Readers  will  easily  see  how  many  gaps  remain  to  be  filled  up. 
To  fill  these  gaps  the  observations  and  experiments  required  are 
not  yet  available.  The  words  of  Hippocrates  are  as  true  now  as 
when  he  wrote  them  more  than  two  thousand  years  ago :6/3ibs  flpa- 

Xvs,  rj  &  Ttyy-n  ^KP^ 
OXFORD,  MAY  1920. 


x  RESPIRATION 

Owing  to  the  aftermath  of  the  war  there  has  been  considerable 
delay  in  printing  the  book,  and  meanwhile  a  good  deal  of  new 
work  has  appeared  on  the  subjects  of  certain  chapters.  Where 
this  could  not  be  incorporated  without  serious  recasting  in  the 
proofs  it  is  referred  to  in  addenda  to  the  chapters  in  question. 

MAY  1921. 


CONTENTS 
PREFACE vii 

CHAPTER  I.  HISTORICAL  INTRODUCTION  i 

Early  theories  of  respiration,  i. — Boyle  and  Mayow,  i. — Black  and  Priestley, 
2. — Lavoisier's  interpretation  of  respiration  and  the  source  of  animal  heat,  2. 
— Mayer  and  the  source  of  vital  energy,  3. — Discoveries  as  to  the  composition  of 
animal  food  and  excreta,  3. — Discoveries  as  to  the  blood  gases  and  the  part  they 
play,  4. — Theories  and  discoveries  as  to  physiological  regulation  of  vital  oxida- 
tion, 4. — Work  of  Liebig,  Voit,  Rubner,  Pfliiger,  and  others,  5. — Discoveries 
as  to  physiological  regulation  of  body  temperature,  6.-^-The  "energy  require- 
ments" of  the  living  body,  6. — The  problem  of  regulation  of  breathing,  8. — 
The  respiratory  center.  Work  of  Legallois  and  others,  8. — The  vagus  nerves  and 
breathing.  Work  of  Hering  and  others,  9. — Chemical  excitation  of  breathing. 
Work  of  Rosenthal  and  others,  10. — Theories  of  "vagus  apnoea"  and  "chemical 
apnoea,"  n. — Conclusions  as  to  various  chemical  and  other  excitants  of  breath- 
ing, 13. — Criticism  of  these  conclusions  and  starting  point  of  the  investigations 
described  in  succeeding  chapters,  14. 

CHAPTER   II.   CARBON   DIOXIDE  AND   REGULATION 
OF  BREATHING     .         .         .         .         .         .         .15 

Effects  of  varying  proportions  of  CO2  and  oxygen  on  breathing  in  man,  15. — 
Importance  of  the  alveolar  air,  16. — Method  of  sampling  the  alveolar  air,  17. 
— relative  constancy  of  the  alveolar  CO2  percentage,  19. — Effects  of  varying 
oxygen  percentage  of  the  alveolar  CO2  percentage,  20. — Effects  of  varying  COa 
percentage  in  the  inspired  air  on  the  alveolar  CO2  percentage,  21. — Extreme 
sensitiveness  of  the  respiratory  center  to  variation  in  alveolar  CO2  percentage, 
22. — Apnoea  after  forced  breathing  is  due  simply  to  lowering  of  alveolar  CO2 
percentage,  24. — Constancy  of  mean  alveolar  CO2  pressure  in  spite  of  great 
variations  in  rate  and  depth  of  breathing,  27. — Rise  of  alveolar  CO2  percentage 
during  muscular  exertion,  2g. — Effects  of  varying  barometric  pressure  on  alve- 
olar CO2  percentage,  30. — Constancy  of  alveolar  CO2  pressure  with  varying 
barometric  pressure,  31. — Individual  differences  in  alveolar  CO2  pressure,  32. 
— The  anatomy  of  bronchioles  and  alveoli,  33. — "Alveolar  air"  is  air  of 
Miller's  "air-sac"  system,  35. — The  "effective"  or  "virtual"  dead  space  in 
breathing,  35. — Great  variations  in  effective  dead  space  with  varying  depth  of 
breathing,  37. — "Alveolar"  and  true  respiratory  quotients,  38. — Errors  due  to 
ignorance  of  the  variations  in  the  effective  dead  space,  39. — Gas  pressures  of 
alveolar  air  and  arterial  blood,  41. — Question  as  to  varying  composition  of 
air  in  different  alveoli,  42. — General  conclusion  from  Chapter  I,  42. 

CHAPTER  III.  THE  NERVOUS  CONTROL  OF  BREATH- 
ING .     43 

Voluntary   and   reflex   disturbances    of   breathing,    43. — Experiments   on   man 


xii  RESPIRATION 

showing  the  non-existence  of  "vagus  apnoea,"  47. — Afferent  vagus  excitations 
coordinate  the  phases  of  breathing,  48. — The  depth  and  vigor  of  breathing  de- 
pend on  the  chemical  stimuli  to  the  respiratory  center,  49. — Effects  of  resistance 
on  the  rhythm  of  breathing,  50. — Artificial  respiration  and  the  vagus  coordina- 
tion of  breathing,  50. — Normal  breathing  and  afferent  nervous  control,  53. — 
Evidence  that  the  activity  of  the  respiratory  center  depends  on  locally  acting 
chemical  stimuli  in  the  medulla  oblongata,  53. — Physiological  significance  of 
this  fact,  54. — Fatigue  of  the  respiratory  center,  56. — The  breathing  in  "sol- 
dier's heart"  and  allied  conditions,  57. — "Neurasthenia"  and  fatigue,  56. — 
Variations  in  individual  susceptibility  to  fatigue  of  breathing,  57. 

CHAPTER  IV.  THE  BLOOD  AS  A  CARRIER  OF  OXYGEN       59 

General  chemical  properties  of  haemoglobin  and  oxyhaemoglobin,  59. — Meth- 
aemoglobin  and  its  properties,  59. — Action  of  ferricyanide  in  liberating  oxygen 
or  CO  from  combination  with  haemoglobin,  60. — Oxyhaemoglobin  and  CO 
haemoglobin  are  molecular  compounds,  61. — The  ferricyanide  method  of  de- 
termining the  oxygen  capacity  of  haemoglobin,  61. — The  oxygen  capacity  of 
haemoglobin  is  exactly  proportional  to  its  coloring  power,  61. — The  Gowers- 
Haldane  haemoglobinometer,  62. — Normal  variations  in  haemoglobin  percentage 
of  blood,  63. — Haemochromogen  and  its  modifications,  64. — Relation  between 
oxygen  capacity  and  iron  of  haemoglobin,  64. — Relation  of  haemochromogen 
to  haemoglobin,  66. — Ferricyanide  method  for  ordinary  blood-gas  determina- 
tions, 66. — Amount  of  available  oxygen  in  human  arterial  blood,  67. — Funda- 
mental importance  of  the  partial  pressure  of  oxygen  in  the  blood,  67. — "Partial 
pressures,"  "vapor  pressures,"  "diffusion  pressures,"  and  "concentrations"  of 
substances  in  the  living  body,  67. — Investigations  of  the  laws  of  dissociation 
of  oxyhaemoglobin  in  blood,  68. — Work  of  Paul  Bert,  Hiifner,  Loewy  and 
Zuntz,  Bohr,  Barcroft,  70. — Effects  of  salts,  COz,  and  acids  or  alkalies,  72. — 
Physiological  importance  of  the  shape  of  the  oxyhaemoglobin  dissociation  curve, 
7 2.-^— Properties  and  dissociation  curves  of  CO  haemoglobin,  72. — Nature  of 
alterations  produced  by  CO2  on  the  dissociation  curves  of  CO  haemoglobin  and 
oxyhaemoglobin,  76. — Relative  affinities  of  oxygen  and  CO  for  haemoglobin, 
74- — Evidence  of  differences  in  the  chemical  structure  of  haemoglobin  in  differ- 
ent individuals  and  species,  77. — Use  of  haemoglobin  for  estimating  partial 
pressures  of  CO  or  oxygen,  79. — Explanation  of  the  peculiarities  of  the  dissocia- 
tion curve  of  oxyhaemoglobin  in  blood,  80. — Equations  for  the  dissociation 
curves,  82. 


CHAPTER  V.  THE  BLOOD  AS  A  CARRIER  OF  CARBON 

DIOXIDE       ........     84 

Amount  of  CO2  in  normal  human  and  dog's  arterial  blood,  84. — Amounts  in 
simple  solution  and  chemical  combination,  85. — The  CO2  is  combined  with 
alkali  as  bicarbonate,  84. — Why  the  bicarbonate  dissociates  appreciably  with  a 
small  fall  in  the  partial  pressure  of  CO2  in  the  blood,  85. — Haemoglobin  and 
other  proteins  act  as  acids  in  the  living  body,  and  do  not  combine  with  CO2, 
though  they  play  a  most  essential  part  in  its  carriage,  88. — The  dissociation 
curve  for  CO2  of  human  blood,  89. — Constancy  of  this  curve  for  the  same  indi- 
vidual, and  relative  constancy  in  different  normal  individuals,  89. — Evidence 
that  oxygen  has  a  chemical  action  in  liberating  CO2  in  the  lungs,  92. — The  de- 


RESPIRATION  xiii 

oxygenation  of  the  blood  in  the  tissues  helps  the  blood  to  combine  with  CO2  and 
thus  partly  prevents  the  pressure  of  COz  from  rising,  90. — CC>2  may  be  given  off 
in  the  lungs  although  the  CO2  pressure  is  lower  in  the  venous  blood  than  in  the 
alveolar  air,  91. — Approximate  mathematical  treatment  of  the  dissociation  curve 
for  CO2,  92. — Effect  of  the  CO2  in  blood  on  the  dissociation  of  oxyhaemoglobin 
in  the  systemic  blood,  94. — The  physiological  buffers  which  prevent  abrupt  rise 
or  fall  of  CO2  pressure  in  the  respiratory  center,  96. — Effects  on  the  alveolar 
CO2  pressure  of  holding  the  breath  or  forced  breathing,  96. — Abruptness  of 
rises  or  falls  of  oxygen  pressure  in  the  respiratory  center,  100. — This  abrupt- 
ness is  the  cause  of  periodic  breathing  when  the  alveolar  oxygen  pressure  is  low, 
103. — Artificial  production  of  periodic  breathing  in  healthy  persons,  103. — 
Why  shortage  of  oxygen  and  consequent  periodic  breathing  do  not  occur  nor- 
mally, 104. — Addendum,  Discussion  of  some  recent  theories  of  the  carriage  of 
CO2  by  blood,  105. — Interchange  of  acid  between  plasma  and  corpuscles,  106. 


CHAPTER  VI.  THE  EFFECTS  OF  WANT  OF  OXYGEN     108 

Immediate  dependence  of  the  body  for  its  oxygen  supply  on  air,  108. — Anox- 
aemia produced  by  lowered  pressure  of  oxygen  in  the  air,  109. — Effects  on  the 
breathing,  109. — These  effects  largely  transitory,  109. — Lowering  of  the  thresh- 
old of  alveolar  CO2  pressure,  but  alveolar  CO2  pressure  still  regulates  the 
breathing,  no. — Variability  of  the  effects  in  different  individuals,  in. — 
Death  from  anoxaemia  caused  by  excessive  removal  of  CO2  from  the  blood,  112. 
— Excess  of  COa  in  the  air  counteracts  the  effects  of  deficiency  of  oxygen,  112. 
— Mere  increase  of  breathing  does  not  diminish  the  anoxaemia,  though  it  dimin- 
ishes the  cyanosis,  114. — The  peculiar  symptoms  produced  by  forced  breathing 
are  apparently  due  mainly  to  anoxaemia,  115. — Subsidiary  effects  of  CO2  in  re- 
lieving anoxaemia,  117. — Periodic  breathing  at  high  altitudes  is  caused  by 
anoxaemia,  117. — Effects  of  anoxaemia  on  the  frequency  of  breathing,  118. — 
Effects  in  causing  fatigue  of  the  breathing,  121. — Effects  of  anoxaemia  on  the 
circulation,  121. — Increase  in  pulse  rate  is  largely  transitory,  123. — Cyanosis 
and  anoxaemia  not  the  same  thing,  125. — Effects  on  the  nervous  system,  125. — 
Insidious  character  of  these  effects,  125. — Effects  on  muscular  power,  senses, 
memory,  and  powers  of  judgment,  126. — Personal  experiences,  128. — Moun- 
tain sickness  and  conditions  of  its  production,  128. — Nervous  after  symptoms 
following  severe  anoxaemia,  129. — After  effects  on  heart,  129. — After  effects 
on  respiratory  center,  130. — Adaptation  to  want  of  oxygen,  130. 


CHAPTER  VII.  THE  CAUSES  OF  ANOXAEMIA     .         .132 

Defective  saturation  of  arterial  haemoglobin,  132. — One  cause  of  this  is 
defective  distribution  of  air  in  the  lungs,  133. — Experimental  proof  and  ex- 
planation of  this,  133. — Effects  of  holding  the  breath,  and  explanation  of  the 
anoxaemia  produced,  141. — Cause  of  difference  between  clinical  Cheyne-Stokes 
breathing  and  periodic  breathing  produced  artificially  in  healthy  persons,  141. 
— Significance  of  rapid  breathing  in  cases  of  illness,  142. — Danger  of  sudden 
attacks  of  restricted  and  rapid  breathing,  143. — Causes  of  anoxaemia  in  em- 
physema, bronchitis,  and  asthma,  145. — Orthopnoea  and  its  causes,  146. — A 
second  cause  of  arterial  anoxaemia  is  defective  pressure  of  oxygen  in  the  in- 
spired air,  146. — Immediate  effects  and  after  effects,  147. — The  percentage 
saturation  of  the  arterial  haemoglobin  is  lower  than  corresponds  to  the  oxygen 


xiv  RESPIRATION 

pressure  of  the  mixed  alveolar  air,  148. — With  the  same  alveolar  oxygen  pres- 
sure there  is  less  anoxaemia  at  low  atmospheric  pressures  than  at  normal  atmos- 
pheric pressure,  148. — Anoxaemia  due  to  hindered  diffusion  of  oxygen  into  the 
blood,  149. — Poisoning  by  lung-irritant  gases,  150. — Arterial  anoxaemia  in 
pneumonia,  150. — Observations  of  Stadie,  Harrop,  and  Meakins,  151. — The 
clinical  administration  of  oxygen,  152. — Description  of  apparatus  for  the  pur- 
pose, 154. — Anoxaemia  during  muscular  exertion,  156. — Experiments  of  Briggs 
on  oxygen  inhalation  during  muscular  exertion,  157. — Anoxaemia  and 
velocity  of  chemical  reaction  in  the  formation  of  oxyhaemoglobin,  158. — 
Anoxaemia  due  to  defective  oxygen-carrying  power  of  the  blood,  158. — Evidence 
that  the  symptoms  of  CO  poisoning  are  due  to  anoxaemia,  160. — CO  is  not 
oxidized  in  the  body,  but  passes  in  and  out  by  the  lungs,  160. — Popular  errors 
as  to  the  effects  of  CO  poisoning  and  anoxaemia  generally,  160. — Relation  be- 
tween percentage  of  CO  in  air  and  percentage  saturation  of  the  blood  with  CO. 
1 60. — Relation  between  percentage  saturation  of  the  blood  and  symptoms,  161. 
— Causes  of  certain  differences  between  the  symptoms  of  CO  poisoning  and 
those  of  anoxaemia  produced  in  other  ways,  162. — Alteration  of  the  dissociation 
curve  of  oxyhaemoglobin  in  CO  poisoning,  165. — Acclimatization  to  CO  poison- 
ing, 1 66. — Occurrence  of  NO  haemoglobin  in  the  body,  166. — Methaemoglobin- 
forming  poisons,  166. — Evidence  that  with  these  poisons  death  is  due  to  anox- 
aemia, 167. — Recovery  from  methaemoglobin-forming  poisons,  167. — Hae- 
molytic  poisons,  168. — Anaemia  and  anoxaemia,  168. — Reasons  why  no  anox- 
aemia is  present  during  rest  in  ordinary  anaemia,  169. — Anoxaemia  due  to  de- 
fective circulation,  169. — Gum-saline  injections  in  defective  filling  of  the  vessels 
with  blood,  170. 

CHAPTER  VIII.  BLOOD  REACTION  AND  BREATHING     171 

Ordinary  physiological  indications  of  maintenance  of  a  normal  blood  reaction, 
*7i' — Walter's  experiments  on  acid  poisoning  and  the  defenses  against  it,  171. 
— Diabetic  coma  and  acid  poisoning,  173. — "Titration  alkalinity"  and  alkalinity 
of  the  blood,  173. — The  "buffer  substances"  in  the  living  body,  174. — Modern 
conceptions  of  alkalinity  and  acidity,  175. — Osmotic  pressure,  molecular  con- 
centration, and  molecular  diffusion  pressure,  176. — lonization  of  molecules,  177. 
— lonization  and  reaction,  177. — Electrometric  measurement  of  reaction,  179. — 
Theories  of  acidosis  and  anoxaemia,  179. — Hasselbalch's  electrometric  de- 
terminations of  relation  of  CO2  pressure  to  reaction  in  blood,  182. — Experiments 
showing  that  variation  of  alveolar  CO2  pressure  in  the  living  body  compensates 
for  variations  in  blood  reaction  which  would  otherwise  occur,  183. — Barcroft's 
experiments  on  the  Peak  of  Teneriffe,  183. — Quantitative  relation  between  varia- 
tions of  breathing  and  of  blood  reaction,  184. — Extreme  delicacy  of  regulation 
of  blood  reaction,  185. — Very  small  difference  between  the  reactions  of  arterial 
and  venous  blood,  185. — Difference  in  reaction  between  oxygenated  and  fully 
reduced  normal  blood,  186. — Error  in  electrometric  method,  188. — Summary  of 
evidence  as  to  the  means  by  which  blood  reaction  is  regulated,  188. Dis- 
turbance of  blood  reaction  by  anoxaemia,  189. — Physiological  evidence  that  the 
blood  becomes  more  alkaline,  189. — Gradual,  but  incomplete,  compensation  for 
this  by  the  kidneys  and  liver,  192.— This  compensation  mistaken  for  an 
"acidosis,"  192. — Relief  of  the  anoxaemia  by  the  compensation,  193. — Com- 
pensatory blood  changes  brought  about  by  exposure  to  excess  of  CO2,  or  by  ex- 
cessive removal  by  CO2  from  the  body,  193. — The  amount  of  "alkaline  reserve" 
in  the  blood  is  no  certain  index  of  "acidosis"  or  "alkalosis,"  194. — Experiments 


RESPIRATION  xv 

on  the  urine  excreted  during  forced  breathing,  195. — True  acidosis  caused  by 
excessive  muscular  exertion,  196. — Disturbance  of  blood  reaction  in  nephritis, 
196. — Ammonium  chloride  acidosis  in  man,  196. — Remarks  on  indirect  methods^ 
used  for  measuring  changes  of  reaction  in  the  blood,  199. — Method  depending 
on  the  dissociation  curve  of  oxyhaemoglobin,  199. — Method  depending  on  ratio 
of  combined  CO2  to  free  CO2  in  blood,  200. — Need  for  more  delicate  methods 
than  we  possess  at  present,  202. — Question  as  to  the  constancy  of  blood  reaction 
during  normal  life,  202. — Action  of  drugs  on  the  regulation  of  blood  reaction, 
204. — Reasons  why  the  alveolar  CO2  pressure  is  not  perfectly  steady  during 
rest,  204. — Effects  of  meats,  204. — Effects  of  starvation  and  carbohydrate-free 
diets,  205. — The  regulation  of  breathing  in  man  during  rest  is  practically 
speaking  regulation  of  blood  reaction,  205. — Addendum.  Recent  literature  on 
acidosis  and  alkalosis,  205. — Definition  of  acidosis  and  alkalosis,  206. — Ex- 
treme delicacy  and  physiological  importance  of  regulation  of  reaction  in  the 
tissues,  207. 


CHAPTER  IX.  GAS  SECRETION  IN  THE  LUNGS  .         .  208 

Question  as  to  active  secretion  of  gas  by  the  lung  epithelium,  208. — Oxygen 
secretion  by  the  swim  bladder  epithelium,  208. — Function  of  the  swim  bladder, 
208. — Biot's  discovery  of  oxygen  secretion,  209. — Experiments  of  Moreau,  Bohr, 
and  Dreser,  210. — Jager's  discovery  of  the  "oval"  in  the  swim  bladder,  211. — 
Histology  of  the  swim  bladder  wall  and  "red  body,"  214. — Probable  function  of 
the  "red  body,"  214. — Gas  secretion  in  Arcella.  Experiments  of  Bles,  216. — 
Implications  of  secretion  generally,  217. — Ideas  of  Johannes  Miiller  on  secre- 
tion, 218. — -Apparent  gas  secretion  in  Corethra  larvae,  220. — Ludwig  and 
Pfliiger  on  gas  secretion  by  the  lungs,  220. — Experiments  of  Bohr  and  Fredericq, 
221. — Method  and  experiments  of  Krogh,  222. — Carbon  monoxide  method  of 
measuring  arterial  oxygen  pressure,  224. — Fallacies  in  earlier  measurements, 
225. — New  experiments  on  animals.  Conclusions,  226. — New  experiments  on 
men.  Method,  229. — Result  that  secretion  is  completely  absent  during  rest 
under  normal  conditions,  but  present  under  conditions  producing  want  of  oxy- 
gen in  the  tissues,  233. — Experiments  after  acclimatization  on  Pike's  Peak,  236. 
— Evidence  of  constant  active  secretion,  237. — Indirect  evidence  of  oxygen 
secretion,  238. — Experiments  of  Briggs,  240. — Experiments  in  a  respiration 
chamber  at  normal  atmospheric  pressure,  241. — Acclimatization  experiments  in 
a  steel  chamber,  242. — Cause  of  difference  between  results  by  carbon  monoxide 
and  aerotonometer  methods,  243. — Reason  why  the  percentage  of  oxygen  satura- 
tion of  the  arterial  blood  is  considerably  less  at  high  altitudes  before  acclimatiza- 
tion than  corresponds  to  the  oxygen  pressure  of  the  alveolar  air,  244. — Bohr's 
method  of  measuring  the  rate  of  diffusion  of  gases  from  the  alveolar  air  into 
the  blood,  245. — Experiments  of  A.  and  M.  Krogh  by  this  method,  246. — 
Paralysis  of  oxygen  secretion  under  pathological  conditions,  247. — Direct  evi- 
dence that  during  hard  muscular  work  at  normal  atmospheric  pressure  diffusion 
of  oxygen  is  quite  insufficient  to  saturate  the  arterial  blood  with  oxygen,  247. — 
Question  of  active  excretion  of  COa  by  the  lungs.  Krogh's  experiments,  247. — 
Reasons  for  suspecting  that  active  secretion  of  COa  may  occur  under  certain 
conditions,  248. — Comparison  of  oxygen  secretion  by  the  lungs  with  glomerular 
secretion  by  the  kidneys,  250. — Reply  to  some  recent  criticisms  of  the  evidence 
for  oxygen  secretions,  251. — Addendum.  Recent  experiments  of  Barcroft  and  his 
co-workers,  253. 


xvi  RESPIRATION 

CHAPTER  X.  BLOOD  CIRCULATION  AND  BREATHING     257 

Intimacy  of  connection  between  circulation  and  breathing,  257. — The  mosl 
immediate  need  for  circulation  is  the  need  for  oxygen  and  for  removal  of  COz, 
257. — The  local  circulation  rates  must  be  correlated  in  the  main  with  these 
needs,  258. — Special  value  of  experiments  on  man,  259. — Experiments  of  Loewy 
and  von  Schrotter  with  lung  catheter,  260. — Experiments  of  Krogh  and  Lind- 
hard  by  the  nitrous  oxide  method,  262. — Yandell  Henderson's  experiments  on 
dogs,  263. — Experiments  on  "heart-lung  preparations,"  264. — New  method  in 
which  the  whole  of  the  lungs  are  used  as  an  aerotonometer,  264. — Results  in 
man  during  rest  and  work,  265. — The  circulation  rate  is  rapid  during  rest,  and 
does  not  increase  in  direct  proportion  to  work,  268. — The  oxygen  consumption 
per  heartbeat  and  its  significance,  269. — The  venous  blood  from  different  parts 
of  the  body,  270. — Significance  of  this  as  regards  the  mixed  venous  blood  under 
different  conditions,  270. — General  conclusion  as  regards  local  regulation  of 
blood  flow,  271. — Yandell  Henderson's  experiments  on  local  circulation  and 
COz  pressure,  272. — Evidence  that  excessive  artificial  respiration  causes  slowing 
of  the  circulation  and  great  local  anoxaemia,  272. — With  moderate  increase  of 
COz  percentage  in  the  inspired  air  the  circulation  does  not  increase  with  the 
breathing,  273. — But  with  great  increase  of  COz  percentage  the  circulation  in- 
creases, 274. — Increase  in  oxygen  pressure  slows  the  circulation,  274. — With 
great  deficiency  of  oxygen  there  is  increase  in  the  circulation,  275. — Effects  of 
forced  breathing  and  muscular  exertion  on  venous  blood  pressure,  275. — Gen- 
eral conclusion  as  to  regulation  of  local  and  general  circulation,  276. — Com- 
parison of  regulation  of  circulation  with  regulation  of  breathing,  277. — Part 
played  by  the  heart  in  the  circulation,  278. — Regulation  of  heart's  action,  278. — 
Coordination  of  contraction  of  muscular  fibres  of  auricles  and  ventricles,  278. — 
Start,  spread,  and  frequency  of  each  contraction,  279. — Regulation  of  filling  of 
ventricles,  279. — Nervous  regulation  of  frequency  of  heartbeat,  279. — Regula- 
tion of  blood  distribution,  281. — Contractility  of  arteries,  veins,  and  capillaries, 
281. — Vasomotor  regulation  of  arterial  and  venous  blood  pressure,  283. — 
Abnormal  defects  in  circulatory  regulation,  284. — Valvular  defects  and  breath- 
ing, 286. — Nervous  defects  and  breathing,  286. — Loss  of  blood  and  its  treat- 
ment by  gum-saline  injections,  287. — The  condition  of  "shock,"  288. — Yandell 
Henderson's  investigations,  288. — Shock  from  absorption  of  poisonous  disin- 
tegration products,  289. — Regulation  of  blood  volume,  haemoglobin,  and  rate 
of  pulse  and  respiration  in  animals  of  different  sizes,  and  after  loss  of  blood  or 
transfusion,  290. — Evidence  that  the  haemoglobin  percentage  of  the  blood  de- 
pends on  the  oxygen  pressure  in  tissue  capillaries,  293. — Chlorotic  "anaemia" 
and  breathing,  297. — Addendum.  Further  experiments  on  the  circulation  in 
man,  298. 

CHAPTER  XI.  AIR  OF  ABNORMAL  COMPOSITION  300 

Outside  air  of  country  and  towns:  effects  of  impurities,  300. — Air  of  occupied 
rooms.  Common  impurities  and  their  effects,  302. — Effects  of  temperature, 
moisture,  and  movement  of  air,  303. — General  standard  of  air  purity,  305. — 
Critical  wet-bulb  temperature,  305. — The  katathermometer,  306. — Escape  of 
lighting  gas  and  conditions  determining  their  danger,  306. — Importance  of  pro- 
portion of  CO  in  lighting  gas,  310. — Air  of  mines.  Abnormal  constituents 
present,  311. — Black  damp:  composition,  sources,  and  properties,  311. — Fire 
damp:  composition,  sources,  and  properties,  313. — Afterdamp  from  explosions 


RESPIRATION  xvii 

causes  death  by  CO  poisoning,  315. — Causes  and  prevention  of  colliery  ex- 
plosions, 316. — Composition  of  pure  afterdamp  and  practical  test  for  CO,  316. 
— Self-contained  breathing  apparatus  for  miners,  318. — White  damp  and  spon- 
taneous heating  of  coal,  319. — Smoke  from  fires  and  blasting:  nitrous  fumes, 
319. — Treatment  of  CO  poisoning,  320. — Wet-bulb  temperature  in  mines,  321. 
— Effects  of  dust  inhalation  in  mines,  322. — Varying  effects  of  different  kinds  of 
dust.  Miner's  phthisis,  322. — Physiology  of  dust  excretion  from  the  lungs,  323. 
— Air  of  wells.  Barometric  pressure  and  dangers  of  well  sinkers,  325. — Oxida- 
tion processes  in  underground  strata,  326. — Air  of  railway  tunnels,  326. — Air 
of  sewers.  Accidental  impurities  and  their  dangers,  327. — Air  of  ships,  329. — 
Lung-irritant  gas  poisoning  in  warfare,  and  treatment,  329. 

CHAPTER  XII.  EFFECTS  OF  HIGH  ATMOSPHERIC 

PRESSURES 334 

Paul  Bert's  work  on  the  physiological  action  of  barometric  pressure,  334. — 
The  diver's  equipment  and  the  method  of  using  it,  335. — The  diving  bell  and  the 
caisson,  336. — Tunneling  in  compressed  air,  337. — Effects  of  air  pressure  on  the 
ears  and  voice,  338. — Effects  due  to  pressure  of  COz  in  diving,  and  their 
avoidance,  339. — Compressed  air  illness  or  "caisson  disease,"  340. — Investiga- 
tions of  Paul  Bert  and  others,  341. — Medical  recompression  chambers,  343. — 
Theory  of  stage  decompression  and  experiments  on  the  subject,  345. — Tables  for 
guidance  of  divers,  350. — Treatment  of  compressed-air  illness,  351. — Diving 
operations  at  a  great  depth  off  Honolulu,  351. — Management  of  air  locks  in 
tunnels,  353. — Paul  Bert's  experiments  on  effects  of  increased  oxygen  pres- 
sure, 355. — Effects  of  oxygen  in  producing  pneumonia,  356. 

CHAPTER  XIII.  EFFECTS  OF  Low  ATMOSPHERIC 

PRESSURES 358 

Occurrence  of  low  atmospheric  pressures  at  high  altitudes.  "Mountain  sickness," 
358. — Summary  of  Paul  Bert's  fundamental  experiments  on  the  pressure  effects 
of  gases,  358. — His  experiment  on  man  in  a  steel  chamber,  360. — Reason  why 
a  given  lowering  of  alveolar  oxygen  pressure  has  less  physiological  effect  at  a 
low  atmospheric  pressure  than  at  ordinary  atmospheric  pressure,  362. — Effect 
of  CO;j  pressure  in  diminishing  the  anoxaemia  of  a  low  atmospheric  pressure, 
362. — Mosso's  "acapnia"  theory,  363. — Acclimatization  to  low  atmospheric 
pressures,  364. — Effects  of  high  altitudes  in  increasing  the  haemoglobin  per- 
centage of  the  blood,  364. — Effect  of  increased  atmospheric  pressure  in  dimin- 
ishing the  haemoglobin  percentage,  365. — Beneficial  effect  of  increased  haemo- 
globin in  anoxaemia,  365. — Increased  breathing  in  acclimatized  persons,  366. 
— Physiological  effect  of  a  mere  increase  of  breathing,  367. — The  acclimatiza- 
tion change  is  a  compensation  of  alkalosis,  369. — Alveolar  COz  pressure  in 
persons  acclimatized  at  various  altitudes,  370. — Conclusions  from  the  Duke  of 
Abruzzi's  Himalayan  Expedition,  372. — Active  secretion  of  oxygen  in  the  lungs 
after  acclimatization,  373. — Relation  of  physical  training  to  power  of  oxygen 
secretion,  373. — History  of  high  ascents  in  balloons,  375. — High  ascent  by 
Glaisher  and  Coxwell  in  1862,  375. — Fatal  ascent  of  the  Zenith  in  1875,  376. 
— High  ascent  with  use  of  oxygen  in  1901,  378. — Experiments  of  von  Schrotter, 
379. — Recent  high  American  aeroplane  ascent,  379. — Limits  of  height  attainable 
with  use  of  ordinary  oxygen  apparatus,  379. — Apparatus  required  for  indefinitely 
great  heights,  380. 


xviii  RESPIRATION 

CHAPTER  XIV.  GENERAL  CONCLUSIONS  .         .         .382 

The  breathing  and  circulation  are  so  regulated  as  to  keep  the  diffusion  pres- 
sures of  oxygen,  and  of  hydrogen  and  hydroxyl  ions,  in  the  tissues  normal,  382. 
— Breathing  and  circulation  are  responses  to  tissue  activity,  and  do  not  pri- 
marily determine  it,  383. — Claude  Bernard  and  the  regulation  of  internal  en- 
vironment, 383. — Diffusion  pressures  and  Bernard's  "conditions  of  life/'sSs. — 
Diffusion  pressure  of  water  on  the  same  footing  as  that  of  other  blood  constitu- 
ents, 384. — The  blood  constituents  are  in  continuous  active  relation  with  the 
living  tissues,  385. — Comparison  of  living  tissue  elements  with  dissociable 
chemical  molecules,  386. — Conception  of  the  living  body  as  the  seat  of  a  system 
of  mutually  dependent  reversible  reactions,  386. — Defects  of  the  mechanistic 
and  "hormone"  theories  of  physiological  inter-connection,  387. — The  dividing 
line  between  biology  and  the  physical  sciences,  388. — The  fundamental  con- 
ception of  biology,  and  the  real  work  of  the  biological  sciences,  389. — This 
work  illustrated  by  the  investigations  detailed  in  previous  chapters,  389. — 
Real  nature  of  organic  identity,  390. — The  existence  of  active  maintenance  of 
organic  identity  is  the  foundation  of  medicine  and  surgery,  as  well  as  of  physiolo- 
gy and  morphology,  391. — Examination  of  the  argument  that  the  physical  con- 
ception of  Nature  is  truer  and  more  scientific  than  the  biological,  392. — The 
previous  question  which  is  fatal  to  the  physical  conception,  394. — Physical 
reality  a  superficial  sensuous  appearance,  394. — In  describing  biological  phe- 
nomena and  putting  her  questions  to  Nature,  biology  must  use  her  own  working 
hypothesis  and  not  those  of  the  physical  sciences,  394. — Nature  as  seen  by  the 
biologist,  396. — Supposed  evolution  from  "inorganic"  conditions,  396. — Indi- 
vidual life  and  life  in  association,  396. — It  is  impossible  to  describe  or  define 
conscious  activity  in  either  physical  or  biological  terms,  397. — Neither  the 
physical  nor  biological  interpretation  of  Nature  is,  in  the  last  resort,  more  than 
a  practical  makeshift,  398. — The  rightful  practical  sphere  of  physiology  does  not 
include  distinctively  conscious  activity,  399. 

APPENDIX  .........  400 

A.  Determination  of  oxygen  capacity  of  blood  haemoglobin  by  ferricyanide,  400. 
— B.  Determination  of  oxygen  capacity  of  blood  haemoglobin  by  haemoglobin- 
ometer,  404. — C.  Determination  of  oxygen  and  carbon  dioxide  in  blood  by  ferri- 
cyanide and  acid,  407. — D.  Colorimetric  determination  of  percentage  saturation 
of  haemoglobin  with  CO,  418. — E.  Determination  of  blood  volume  in  man 
during  life  by  CO,  424. 


CHAPTER  I 
Historical  Introduction. 

IN  the  history  of  physiological  discovery  the  growth  of  knowledge 
as  to  the  physiology  of  breathing  was  comparatively  late.  Before 
the  middle  of  the  seventeenth  century  hardly  anything  was  known 
about  breathing  except  its  muscular  mechanism  and  the  facts 
that  if  the  breathing  of  a  man  or  higher  animal  is  interrupted 
for  more  than  a  very  short  time  death  ensues,  and  that  the  breath- 
ing is  increased  by  exertion  and  by  some  diseases.  The  discovery 
by  Harvey  of  the  circulation  threw  no  positive  light  on  the  physi- 
ology of  breathing,  and  it  was  still  generally  believed  that  the 
main  function  of  respiration  is  to  cool  the  blood.  Progress  was 
impossible  without  corresponding  progress  in  chemistry, 

The  first  beginnings  of  a  better  knowledge  date  from  the  work 
at  Oxford  of  Robert  Boyle1  and  Mayow2  a  young  doctor.  Boyle 
showed  with  the  air  pump  that  air  is  necessary  to  life,  and  Mayow 
investigated  and  compared  together  the  influences  of  niter  in  the 
combustion  of  gunpowder,  and  of  air  in  respiration  and  ordinary 
combustion  in  air.  He  drew  the  conclusion  that  in  all  of  these 
processes  a  "nitro-aerial  spirit"  combines  with  "sulphur"  (com- 
bustible matter).  As  regards  respiration  he  concluded  that  the 
nitro-aerial  spirit  is  present  in  limited  proportion  in  air,  and  is 
absorbed  from  the  air  in  the  lungs  by  the  blood,  carried  by  the 
circulation  to  the  brain,  where  it  is  separated  off  in  the  ventricles, 
and  thence  passes  down  the  supposed  nerve-  tubules  to  the  muscles, 
where  it  unites  with  "sulphur"  and  produces  muscular  contraction 
by  the  resulting  explosions.  He  explained  the  increased  breathing 
which  accompanies  muscular  exertion  as  a  necessary  accompani- 
ment of  the  increased  consumption  of  the  nitro-aerial  spirit. 

It  will  thus  be  seen  that  he  had  practically  discovered  oxygenr 
in  so  far  as  the  rudimentary  chemical  ideas  which  he  had  formed 
permitted  the  discovery.  He  had  also  formed  a  sound  physiological 
conception  of  the  relation  between  muscular  work  and  increased 
breathing.  Mayow's  conception  of  oxygen  passing  down  the 

1  Boyle,  New  ex-pertinents  physico-mechanical,  touching  the  Spring  of  the  Air, 
Oxford,  1666.  Particularly  Experiments  XL  and  XLI,  with  the  accompanying 
"Digression  containing  some  Doubts  touching  Respiration." 

51  Mayow,  Tractatus  Quinque  Meciico-physici,  Oxford,  1673.  In  particular 
Tractatus  II,  De  Respiratione  (26.  Edition). 


2  RESPIRATION 

nerves  was  of  course  only  a  modification  of  the  idea  then  current, 
and  elaborated  by  Descartes  among  others,  that  muscular  con- 
traction depends  upon  the  "animal  spirits"  passing  down  the 
supposed  nerve  tubules  from  the  brain.  This  conception  was  ap- 
parently confirmed  by  the  effects  of  cutting  or  ligaturing  nerves; 
and  Lower,8  another  Oxford  physician,  performed  the  striking 
experiment  of  completely  disturbing  the  action  of  the  heart  by  a 
ligature  on  the  vagus  nerve.  He  had  stumbled  upon  inhibition 
and  misinterpreted  it  in  favor  of  Mayow's  theory. 

About  the  same  time  another  significant  observation  was  made 
by  Hooke,4  the  Secretary  of  the  Royal  Society.  He  found  that 
when  the  chest  of  an  animal  was  opened  so  that  the  lungs  col- 
lapsed, it  could  be  revived  and  kept  alive  by  artificial  respiration, 
and,  if  holes  were  pricked  in  the  lungs  so  that  air  could  pass 
through  them,  the  animal  could  still  be  kept  alive  if  a  stream  of 
air  was  continuously  blown  through  the  lungs,  although  they  did 
not  move. 

The  foundations  thus  seemed  to  be  laid  of  our  present  knowl- 
edge of  the  physiology  of  breathing;  but  unfortunately  the  sig- 
nificance of  the  discoveries  made  at  Oxford  was  not  appreciated, 
and  indeed  the  study  of  physiology  and  other  branches  of  natural 
science  there  was  practically  allowed  to  die  out  for  the  succeeding 
two  hundred  years. 

The  next  important  step  in  connection  with  respiration  was 
the  discovery,  about  the  middle  of  the  eighteenth  century,  by 
Joseph  Black  of  Edinburgh,  that  "fixed  air"  (carbon  dioxide) 
which  he  had  found  to  be  liberated  by  acids  from  mild  alkalies 
(carbonates)  is  given  off  by  the  lungs  in  respiration.  Priestley 
discovered  soon  afterward  that  what,  in  accordance  with  Stahl's 
phlogiston  theory,  he  called  "dephlogisticated  air"  (oxygen)  dis- 
appears both  in  ordinary  combustion  and  in  animal  respiration, 
while  it  is  produced  by  green  plants  in  sunlight.  Lavoisier  then 
followed  up  Black's  and  Priestley's  work  by  showing  that  in 
combustion  what  he  for  the  first  time  called  oxygen  combines 
with  carbon  and  other  substances,  and  that  carbon  dioxide  is 
produced  by  the  combination  of  carbon  and  oxygen,  while  water 
is  produced  by  the  combination  of  hydrogen  and  oxygen.  He  and 
Laplace5  also  showed  that  the  carbon  dioxide  produced  by  an 
animal  is  nearly  equivalent  to  the  oxygen  consumed,  and  that 

"Lower,  Tractatus  de  Corde,  p.  86,  1669. 

4  Hooke,  Phil.  Trans.,  II,  p.  539,  1667.  Hooke  had  been  assistant  to  Willis 
and  Boyle  at  Oxford. 

"Lavoisier  and  Laplace,  Memoir es  de  I'Academie  des  Sciences,  p.  337,  1780. 


RESPIRATION  3 

the  amount  of  heat  formed  by  an  animal  is  nearly  equivalent  to 
that  formed  in  combustion  of  carbon  when  an  equal  quantity  of 
oxygen  is  consumed  in  respiration  and  combustion.  He  thus  made 
it  clear  that  in  the  living  body,  just  as  in  combustion,  oxygen 
combines  with  carbon  and  other  substances,  producing  carbon 
dioxide  and  other  oxidation  products :  also  that  this  combination 
is  the  source  of  animal  heat. 

He  found  in  the  course  of  experiments  on  man  that  during 
muscular  work  the  consumption  of  oxygen  and  output  of  carbon 
dioxide  is  increased.  Curiously  enough,  he  expresses  regret  that 
this  should  be  so,  as  the  laboring  classes,  who  have  least  money 
for  buying  food,  consume  more  food  than  those  who  are  better 
off.6  The  essential  connection  between  physiological  work  and 
consumption  of  oxygen  was  still  hidden  from  him,  although,  as 
already  seen,  Mayow  had  fairly  correct  ideas  on  this  subject. 
It  was  not  until  1845  that  Mayer,7  a  German  country  doctor, 
pointed  out  in  connection  with  the  general  formulation  of  the 
doctrine  of  conservation  of  energy,  that  in  living  animals,  as  in 
steam  engines,  ordinary  kinetic  energy  as  well  as  heat  has  its 
source  in  the  potential  energy  liberated  in  the  process  of  oxida- 
tion. Oxidation  is  thus  the  ultimate  source  of  the  energy  of  animal 
movements.  Every  exact  experiment  made  since  then  on  this 
subject  has  confirmed  Mayer's  conclusion,  and  the  increased 
consumption  of  oxygen  during  muscular  work  became  as  intelli- 
gible as  it  was  on  Mayow's  crude  theory. 

The  discoveries  with  regard  to  the  chemistry  of  respiration 
raised  the  further  question  as  to  what  the  exact  nature  of  the 
combustible  material  is,  and  where  the  combination  of  oxygen 
with  combustible  matter  occurs.  As  regards  the  first  question  it 
was  evident  that  since  on  an  average  the  composition  of  the  adult 
living  body  remains  constant,  and  the  excreta,  as  compared  with 
the  food  taken,  contain  very  little  combustible  material,  the 
material  oxidized  must  correspond  to  the  oxidizable  matter  of 
the  food.  This  material  was  classified  by  Prout  as  belonging  almost 
entirely  to  one  or  other  of  three  groups  of  substances,  known  now 
under  the  names  of  proteins,  carbohydrates,  and  fats.  Of  these 
the  former  alone  contains  nitrogen,  which  is  excreted  in  the  urine 
in  the  form,  mainly,  of  urea  when  the  protein  is  oxidized.  Only 
water  and  carbon  dioxide  are  formed  in  the  oxidation  of  carbo- 

8  Lavoisier  and  Sequin,  Mem.  de  I'Acaci.,  p.  185,  1789. 

7  Mayer,  Die  orgamsche  Bewegung  in  threm  Zusammenhange  mit  dem  Stoft- 
•wechsel,  Heilbronn,  1845. 


4  RESPIRATION 

hydrates  or  fats,  and  by  the  ratios  and  amounts  in  which  nitrogen 
compounds  and  carbon  dioxide  are  excreted  and  oxygen  consumed 
we  can  calculate  how  much  protein,  carbohydrate,  and  fat  is 
being  consumed  in  the  body. 

As  regards  the  second  question  there  was  for  long  much  doubt. 
It  was,  however,  definitely  shown  by  Magnus8  in  1845  tnat  mucn 
gas  is  liberated  from  blood  on  exposing  it  to  a  vacuum,  and  that 
less  oxygen  and  more  carbon  dioxide  are  given  off  from  venous 
than  from  arterial  blood.  The  mercurial  blood  gas  pump  was 
then  gradually  perfected,  mainly  by  Lothar  Meyer,  Ludwig,  and 
Pfliiger ;  and  it  was  gradually  established  that  the  oxygen  which 
disappears  in  the  lungs  is  taken  up  by  the  blood  almost  entirely 
in  the  form  of  a  loose  chemical  compound  with  haemoglobin,  the 
colored  albuminous  substance  in  the  red  corpuscles.  This  compound 
yields  up  part  of  its  oxygen  as  the  blood  passes  round  the  systemic 
circulation,  and  returns  to  the  lungs  for  a  fresh  charge,  the  charg- 
ing being  due  to  the  higher  partial  pressure  of  oxygen  in  the 
lungs,  while  the  partial  discharging  in  the  systemic  circulation 
is  due  to  the  lower  partial  pressure  there  in  consequence  of  con- 
sumption of  oxygen.  The  discharging  is  accompanied  by  a  change 
of  color  from  scarlet  to  dark  purple.  Similarly  carbon  dioxide  is 
taken  up  mainly  in  the  form  of  a  loose  chemical  combination  with 
alkali,  and  discharged  in  the  lungs  as  a  consequence  of  the  lower 
partial  pressure  of  the  gas  in  the  lungs.  For  a  considerable  time 
there  was  much  doubt  as  to  how  far  the  actual  oxidation  occurs  in 
the  blood  or  in  the  tissue  elements;  but  the  investigations  of 
Pfliiger9  about  1872  showed  clearly  that  practically  all  the  oxida- 
tion occurs  in  the  tissues. 

So  far  I  have  discussed  from  an  abstract  physical  and  chemical 
standpoint  the  main  outlines  of  discovery  relating  to  respiration. 
It  is  now  necessary  to  consider  these  discoveries  more  closely,  and 
from  a  physiological  standpoint.  For  a  long  time  the  brilliance 
of  Lavoisier's  discovery  as  to  the  relation  between  respiration  and 
animal  heat  carried  physiologists  to  some  extent  off  their  balance, 
as  it  came  to  be  believed  that  heat  production  is  a  more  or  less 
blind  mechanical  process  under  no  direct  organic  control,  and 
presumably  dependent  simply  upon  the  supply  of  oxygen  and 
oxidizable  material.  Thus  Liebig,  who  was  not  only  a  great 
chemist  but  also  a  great  chemical  physiologist,  concluded  that 
every  increase  in  the  food  consumed  or  the  amount  of  oxygen 

8  Magnus,  Annalen  der  Physik,  XL,  1838,  and  LXVI,  1845. 

9  Pfliiger,  Pjliiger's  Archrv,  VI,  p.  43,  1872. 


RESPIRATION  5 

introduced  into  the  lungs  must  increase  the  rate  of  oxidation  and 
heat  production.10  This  conclusion  seemed  to  be  confirmed  when 
he  introduced  his  well-known  method  for  the  determination  of 
urea  in  urine  and  it  was  found  that  every  increase  in  the  amount 
of  nitrogenous  food  eaten  was  followed  by  a  corresponding  in- 
crease in  the  amount  of  urea  excreted,  although  during  complete 
starvation  the  excretion  of  urea  was  not  diminished  below  a  certain 
minimum.  He  inferred  that  it  is  only  the  "vital  force"  which  pro- 
tects the  body  against  indefinite  oxidation,  and  that  when  more 
food  is  introduced  than  is  really  required  this  protection  is  not 
extended,  so  that  the  food  material  falls  a  prey  to  oxygen.  In 
assuming  this  influence  of  the  "vital  force"  he  was  only  applying 
to  the  phenomena  of  physiological  oxidation  the  ideas  held  by 
the  majority  of  contemporary  physiologists. 

When,  however,  the  phenomena  of  physiological  oxidation 
came  to  be  studied  more  closely  by  Bidder  and  Schmidt,  Voit,  and 
other  physiologists,  it  was  found  that  although  the  excretion  of 
urea  might  fall  greatly  during  starvation  there  was  very  little 
fall  in  the  consumption  of  oxygen.  It  thus  became  evident  that  any 
diminution  in  the  consumption  of  protein  was  accompanied  by 
increase  in  consumption  of  the  fat  and  of  any  carbohydrate 
remaining  in  the  body.  Further  investigation  of  the  ratios  in  which 
protein,  carbohydrate,  and  fat  replaced  one  another  in  the  oxida- 
tions occurring  in  the  body  resulted  in  the  striking  discovery  by 
Rubner  that  within  wide  limits  of  variation  in  their  supply  to  the 
body  they  replace  one  another  in  proportion  to  the  energy  which 
they  liberate  in  their  oxidation  within  the  body.11  Thus  I  gram  of 
fat  furnishes  as  much  energy  as  2%  grams  of  protein  or  carbohy- 
drate, and  I  gram  of  fat  from  the  reserve  in  the  body  takes  the 
place  of  2*4  grams  of  protein  or  carbohydrate  when  the  supply 
of  the  latter  in  the  food  is  cut  off.  The  idea  that  the  rate  of  oxida- 
tion in  the  living  body  is  determined  by  the  rate  of  food  supply 
is  thus  erroneous.  On  the  contrary  the  oxidation  is  regulated  with 
marvelous  accuracy  in  accordance  with  its  energy  value  in  satis- 
faction of  what  are  commonly  called  the  "energy  requirements" 
of  the  body.  Rubner's  discovery  is  one  of  the  main  physiological 
foundations  of  scientific  dietetics. 

Just  as  the  rate  of  physiological  combustion,  other  things  being 
equal,  is  not  determined  in  the  higher  organisms  by  the  supply  .of 
food  material,  so  it  is  not  determined  by  the  abundance  of  the 

10Liebig,  Letters  on  Chemistry,  Third  English  Edition,  p.  314,   1855. 
"Rubner,  Zeitschr.  f.  Biologie,  XIX,  p.  313,  1883. 


6  RESPIRATION 

oxygen  supply.  Lavoisier  himself  and  afterwards  Regnault  and 
Reiset  found  that  a  warm-blooded  animal  breathing  pure  oxygen 
consumes  no  more  oxygen  than  an  animal  breathing  ordinary 
air;  and  subsequent  investigations  have  shown  that  the  oxygen 
percentage  in  air  has  to  be  reduced  very  low  before  the  oxy- 
gen consumption  is  diminished.  Pfliiger  also  found  that  oxidation 
in  the  tissues  is  within  wide  limits  independent  of  the  rate  of  supply 
of  oxygen  through  the  blood  circulation.  We  are  thus  again  face 
to  face  with  "physiological  requirements." 

When  temperature  and  heat  production  in  the  living  body  came 
to  be  studied  physiologically  the  first  striking  fact  discovered 
was  that  however  much  the  external  temperature  might  vary 
within  wide  limits,  the  body  temperature  of  warm-blooded  ani- 
mals remained  practically  the  same  during,  health.  Similarly, 
although  the  heat  production  might  be  increased  several  times 
by  muscular  exertion  there  was  no  material  increase  of  body 
temperature,  and  it  became  quite  evident  that  the  rise  of  tempera- 
ture in  fever  is  not  due  to  increased  heat  production,  but  to  dis- 
turbance in  the  nervous  regulation  of  heat  discharge  from  the 
body.  Finally,  when  the  influence  of  variations  in  external  tem- 
perature on  heat  production  in  the  body  was  measured,  it  was 
found  by  a  succession  of  observers,  including,  besides  Lavoisier,12 
Crawford  in  1788,  and  Pfliiger  and  others  in  more  recent  times, 
that,  particularly  in  small  animals,  a  lowering  of  external  tem- 
perature evokes  through  the  influence  of  the  nervous  system  a 
rise  in  heat  production,  so  that  heat  production  becomes  subservi- 
ent to  the  maintenance  of  body  temperature.  This  maintenance 
is  therefore  one  of  the  factors  determining  physiological  energy 
requirements. 

When  we  inquire  what  determines  the  energy  requirements  of 
the  body  as  a  whole  we  '  nd  that  the  results  of  investigation  point 
us  towards  a  numbei  of  associated  conditions  which  we  can 
identify  one  by  one  by  observation  or  experiment,  but  which  ordi- 
narily occur  in  conjunction  with  one  another,  and  on  an  average 
remain  very  constant.  Thus  the  activity  of  the  nervous  system  in 
determining  various  forms  of  muscular  and  glandular  activity 
constitutes  one  of  the  chief  factors.  But  the  activities  of  the 
nervous  system  are  themselves  subject  to  control  in  the  form  of 
what  we  call  on  the  one  hand  "fatigue,"  or  on  the  other  "exuber- 
ance of  spirits,"  finding  its  expression  in  man  in  games  and  what 
appear  at  first  sight  to  be  mere  "luxus"  activities  of  all  kinds. 

u  Pfluger,  Pfluger's  Archw,  XII,  p.  282,  1876. 


RESPIRATION  7 

Hence  apart  from  seasonal  variations  the  daily  nervous  activities 
are  pretty  constant  in  total  amount. 

Although  the  internal  body  temperature  is  actually  very  con- 
stant, yet  a  very  moderate  actual  rise  or  actual  fall  in  body 
temperature  is  sufficient  to  increase  or  diminish  oxidation  very 
materially.  In  fever,  for  instance,  the  oxidation  in  the  body  is 
greater  than  it  would  be  without  the  rise  of  temperature  but  with 
other  conditions  the  same.  The  oxidation  in  fever  is,  however, 
only  a  fraction  of  that  during  even  very  moderate  exertion. 

When  we  examine  still  more  closely,  and  in  the  light  of  the  facts 
which  are  continuously  becoming  revealed  by  pathology  and 
pharmacology,  we  begin  to  realize  that  "energy  requirements" 
depend  on  an  infinite  multitude  of  associated  "normal  conditions." 
An  upset  in  the  proportion  of,  say,  calcium  or  potassium  in  the 
blood,  or  in  that  of  substances  produced  in  minute  amounts  in 
one  or  other  of  the  "ductless  glands"  or  supplied  to  the  body 
along  with  the  other  main  constituents  in  ordinary  food,  will 
dramatically  end  "energy  requirements"  by  that  mysterious  phe- 
nomenon which  we  call  death*  and  which  we  are  so  familiar  with 
that  we  almost  cease  to  speculate  about  its  nature. 

At  first  sight  death  may  seem  to  become  intelligible  when  we 
find  that  in  the  higher  animals  its  immediate  cause  is  want  of 
oxygen  in  the  tissues  owing  to  interruption  of  the  circulation  or 
breathing.  But  further  examination  shows  us  that  death  is  no  mere 
stoppage  of  an  engine  owing  to  lack  of  air  or  fuel,  but  also  total 
ruin  of  what  we  took  to  be  machinery.  It  is  a  mysterious  dissolu- 
tion in  the  association  together  of  the  infinitely  complex  group  of 
normals  which  constitute  the  life —  the  <£wrcs  —  of  an  organism ; 
and  an  examination  of  the  fragments  left  has  thrown  no  light  on 
why  the  association  should  have  existed  at  all,  or  endured  so  long. 
The  outward  form  and  internal  arrangenent  and  composition  of 
the  dead  body  tell  their  story  of  life  to  him  who  can  interpret  their 
hieroglyphics ;  but  there  is  no  life  visible.  The  gulf  between  the 
dead  and  the  living  is  a  gulf  across  which  our  present  intellectual 
vision  does  not  reach,  and  we  only  deceive  ourselves  when  we 
sometimes  imagine  that  it  does.  Thus  when  we  ask  what  determines 
those  "energy  requirements"  which  determine  consumption  of 
oxygen  and  output  of  carbon  dioxide  in  the  living  body,  the  only 
answer  we  can  at  present  elicit  from  experimental  investigation 
is  that  the  energy  requirements  are  one  side  of  the  <£wris  of  the 
organism.  To  those  who  object  that  the  <f>v<ris  is  a  mere  name, 
and  that  physiology  must  be  simply  physics  and  chemistry  I  can 


8  RESPIRATION 

only  reply,  following  the  example  of  Hippocrates  who  protested 
against  the  intrusion  of  abstract  philosophical  speculations  into 
medicine,  that  there  can  be  no  doubt  about  the  existence  of  the 
associated  and  persistent  group  of  appearances  which  the  word 
<£v<ris  designates  when  applied  to  life.  If  we  ignore  this  we  reject 
the  one  thing  which  gives  us  that  grasp  of  biological  phenomena 
which  enables  us  to  predict  them,  and  renders  a  scientific  treatment 
of  biology  and  medicine  possible. 

The  immediate  subject  of  this  book  is  the  side  of  physiology 
which  concerns  the  means  by  which  the  supply  of  oxygen  and 
removal  of  carbon  dioxide  are  so  carried  out  and  regulated  that 
physiological  requirements  are  met.  That  this  supply  and  removal 
are  through  the  lungs  and  blood  has  already  been  pointed  out; 
but  the  development  of  knowledge  as  to  the  means  of  regulation 
must  now  be  traced.  Much  difficulty  arises,  however,  from  the 
fact  that  the  problem  itself  was  only  recently  realized  with  any 
clearness.  Respiration  and  circulation  have  been  to  a  large  extent 
treated  as  if  the  requirements  of  the  body  were  on  the  whole 
constant.  Actually,  however,  the  consumption  of  oxygen  and 
production  of  carbon  dioxide  fluctuate  greatly.  A  heavy  exertion, 
for  instance,  will  increase  tenfold  the  consumption  of  oxygen  and 
output  of  carbon  dioxide  for  the  whole  body,  and  must  certainly 
increase  in  a  far  higher  ratio  the  consumption  and  output  of  the 
muscles  actually  at  work. 

It  has  of  course  been  known  from  the  earliest  times  that  muscu- 
lar activity  causes  great  increase  in  the  depth  and  frequency  of 
the  breathing,  and  that  rebreathing  the  same  air  has  a  similar 
effect;  but  the  very  familiarity  of  these  facts  seems  to  have  led 
to  a  relative  neglect  of  the  problem  of  how  the  respiratory  activi- 
ties are  regulated.  An  undue  specialism  has  led  to  the  investiga- 
tion of  each  form  of  bodily  activity  as  if  it  were  something 
separable  from  other  bodily  activities,  and  not  a  physiological 
activity.  Further  confusion  has  arisen  through  the  roughness  of 
many  of  the  experiments  made  on  animals,  and  corresponding 
failure  to  detect  the  delicacy  of  physiological  regulation. 

In  181 1  it  was  discovered  by  Legallois  that  if  a  portion  of  tissue 
definitely  localized  in  the  medulla  oblongata  is  destroyed  respira- 
tion ceases  and  death  ensues.13  This  part  of  the  medulla  has  come 
to  be  known  as  the  respiratory  center;  and  round  the  responses  of 
this  "center"  to  various  nervous  and  other  stimuli  the  physiologi- 
cal investigation  of  breathing  has  been  focused. 

"Legallois,  Experiences  sur  la  principe  de  la  vie,  Paris,   1812. 


RESPIRATION  9 

It  was  found  by  Legallois  and  subsequent  investigators  that  the 
nervous  connections  both  above  and  below  the  respiratory  center 
can  be  successively  severed  without  preventing  the  rhythmic  dis- 
charges of  inspiratory  and  expiratory  impulses  except  in  so  far  as 
efferent  nerves  connected  with  the  center  are  cut  off  from  it.  Thus 
the  rhythmic  discharges  of  the  center  are  not  dependent  on  afferent 
nervous  impulses  and  continue  regularly  so  long  as  normal  arterial 
blood  is  supplied  to  it.  In  this  sense  the  action  of  the  center  is 
automatic.  On  the  other  hand  the  mode  of  action  of  the  center  is 
much  affected  by  nervous  stimuli. 

In  the  first  place  its  action  is  to  a  large  extent  under  voluntary 
control.  Thus  the  breathing  can  easily  be  suspended  for  about  a 
minute,  and  in  the  actions  of  speaking,  singing,  etc.,  is  greatly 
interfered  with.  The  rate  and  depth  of  breathing  are  also 
under  voluntary  control,  and  may  be  much  affected  by  emotion. 
Consciously  perceived  stimuli  of  all  kinds  may  also  affect  the 
breathing — particularly  stimuli  affecting  the  air  passages.  The 
irregularity  and  variability  of  the  breathing  owing  to  all  these 
causes  tended  to  direct  the  attention  of  physiologists  away  from 
the  central  problem  of  how  the  breathing  responds  to  fundamental 
physiological  requirements. 

It  was  soon  discovered  that  apart  from  consciously  felt  stimuli 
the  breathing  is  specially  affected  by  afferent  stimuli  conducted 
by  the  vagus  nerve.  Early  last  century  it  was  noticed  that  when  the 
vagus  nerves  are  severed  the  breathing  becomes  less  frequent  and 
deeper;  and  on  stimulating  the  vagi  various  marked  effects,  de- 
pending on  the  strength  of  stimulus,  were  found  to  be  produced 
on  the  breathing. 

In  1868  Hering  and  Breuer14  made  the  striking  discovery  that 
on  mechanically  interrupting,  at  the  end  of  inspiration,  the  ex- 
pulsion of  air  from  the  lungs  the  rhythm  of  respiratory  effort  is 
interrupted  for  a  time,  until  at  last  this  interruption  is  broken  by 
an  inspiratory  effort,  followed  by  alternating  expiratory  and  in- 
spiratory efforts  showing  that  the  center  has  renewed  its  rhythmic 
activity.  Similarly  if  at  the  end  of  expiration  air  is  prevented  from 
entering  the  lungs  there  is  an  interruption  before  the  center  re- 
turns to  its  normal  rhythmic  activity.  These  effects  are  completely 
absent  if  the  vagi  have  been  divided.  The  slow  rhythmic  dis- 
charges of  the  center  go  on  quite  independently  of  whether  the 
inflation  or  deflation  of  the  lungs  is  prevented  or  not. 

"Hering  and  Breuer,  Sitzber.  d.  Wiener  Akad.,  Math-natural.  Cl.  (2),  LVII, 
p.  672  and  LVIII,  p.  909,  1868. 


10  RESPIRATION 

It  was  evident  from  these  experiments,  and  from  the  marked 
slowing  and  deepening  of  breathing  after  the  vagi  are  cut,  that 
distention  of  the  lungs  stimulates  the  nerve  endings  of  the  vagi 
in  the  lungs  in  such  a  way  as  to  terminate  inspiration  and  initiate 
expiration,  while  deflation  of  the  lungs  produces  a  corresponding 
stimulus  acting  so  as  to  terminate  expiration  and  initiate  inspira- 
tion. Thus  inspiration  seems  to  be  the  cause  of  expiration,  and 
expiration  of  inspiration.  Hering  described  this  as  the  "self-regu- 
lation" of  breathing. 

Another  series  of  observations  relates  to  chemical  stimulation 
of  the  respiratory  center.  It  was  found  that  if  air  containing  very 
little  oxygen  is  breathed,  or  a  small  volume  of  ordinary  air  is 
repeatedly  rebreathed,  great  panting  ensues,  followed  by  general 
convulsions  and  final  cessation  of  breathing.  The  same  result  was 
found  by  Kiissmaul  and  Tenner  to  follow  if  the  blood  supply  to 
the  brain  is  completely  cut  off,  so  that  the  blood  remaining  in  the 
vessels  becomes  venous.  The  respiratory  center  is  thus  first  stimu- 
lated to  excessive  action  by  imperfectly  oxygenated  or  venous 
blood,  and  later  becomes  exhausted  and  finally  ceases  to  act.  But 
another  most  significant  fact  was  definitely  discovered  by  Rosen - 
thai  in  i862.15  If  in  an  animal  artificial  respiration  is  pushed  so 
that  the  ventilation  of  the  lungs  is  abnormally  great  the  activity 
of  the  respiratory  center  ceases  entirely  for  a  time,  and  this 
condition  he  designated  as  apnoea.  In  most  persons  apnoea  can  be 
produced  easily  by  voluntarily  forcing  the  breathing  for  a  short 
time.  After  a  few  deep  and  rapid  breaths  it  will  be  noticed  that 
all  natural  tendency  to  breathe  ceases  for  a  time. 

These  observations  suggested  that  ordinary  breathing  is  de- 
termined by  the  degree  of  arterialization  of  the  blood  supplying 
the  respiratory  center.  If  the  degree  of  arterialization  is  dimin- 
ished the  breathing  is  increased,  and  vice  versa,  so  that  the 
respiratory  center  automatically  maintains  a  normal  degree  of 
arterialization.  When  the  venous  blood  is  arterialized  in  the  lungs 
two  changes  occur,  as  we  have  already  seen.  The  blood  takes  up 
oxygen,  and  also  loses  carbonic  acid.  It  might  be  one  or  the  other, 
or  else  both,  of  these  changes  that  determines  the  activity  of  the 
respiratory  center.  The  most  immediately  evident  change  in  the 
blood  during  its  passage  through  the  lungs  is  its  change  in  color 
from  a  bluish  to  a  bright  scarlet  color,  and  this  change,  as  already 
seen,  is  due  solely  to  its  oxygenation  and  not  to  loss  of  carbonic 
acid.  We  thus  naturally  tend  to  think  of  blue  blood  as  venous  and 

"Resentful,  Z>«*  At**mb*totg**g**,  1862. 


RESPIRATION  II 

scarlet  as  arterial ;  and  with  the  blood  pump  we  can  easily  prove 
that  the  scarlet  blood  contains  more  dissociable  oxygen  than  the 
blue. 

Rosenthal  came  to  the  conclusion  that  it  is  solely  or  almost 
solely  in  virtue  of  its  varying  oxygen  content  that  the  blood 
stimulates  the  respiratory  center  or  not.18  Careful  blood-gas  de- 
terminations showed  that  when  apnoea  had  been  produced  by 
forced  ventilation  of  the  lungs  the  arterial  blood  contained  a  little 
more  oxygen.  On  the  other  hand,  when  oxygenation  was  rendered 
incomplete  by  letting  an  animal  breathe  air  very  poor  in  oxygen 
there  was  an  immediate  great  increase  in  the  breathing,  although 
the  discharge  of  carbonic  acid  was  in  no  way  interfered  with. 
Moreover,  when  air  containing  a  very  large  excess  of  CO2  was 
breathed  by  an  animal  the  rate  of  breathing  remained  normal. 
Rosenthal  also  brought  forward  other  evidence  which  appeared 
to  point  in  the  same  direction ;  but  the  weak  point  in  his  argument 
was  the  fact  that  there  is  no  apnoea  when  pure  oxygen  is  breathed, 
although  the  arterial  blood  contains  a  good  deal  more  oxygen 
than  usual.  The  truth  is  that  he  had  been  misled  by  the  fact  that  a 
very  high  percentage  of  CO2  in  the  air  breathed  has  a  narcotic 
effect,  so  that  the  breathing,  which  is  in  reality  increased  at  first 
by  raising  the  percentage  of  CO2  in  the  air  of  the  lungs,  quiets 
down  again  when  the  percentage  becomes  very  high.  Pfliiger  and 
Dohmen17  showed  that  both  excess  of  CO2  (provided  that  the  CO2 
is  not  in  too  great  excess)  and  want  of  oxygen  excite  the  respira- 
tory center. 

A  further  fact,  discovered  originally  by  Traube,18  but  often 
overlooked  by  subsequent  investigators,  was  that  apnoea  could 
be  produced  even  by  a  gas  such  as  nitrogen  or  hydrogen,  in  which 
no  oxygen  was  present.  Thus  if  apnoea  is  due  to  "over-arterializa- 
tion"  of  the  arterial  blood  it  can  be  produced  by  the  simple  re- 
moval of  CO2,  whether  or  not  the  oxygen  is  also  diminished, 
although  the  artificial  ventilation  of  the  lungs  must  be  much  more 
vigorous  if  apnoea  is  produced  in  the  absence  of  oxygen. 

Meanwhile  another  theory  of  apnoea  was  put  forward,  and 
has  led,  as  will  be  shown  later,  to  the  utmost  confusion  and  com- 
plete misinterpretation  of  the  facts.  When  the  lungs  are  distended 
there  is,  as  already  mentioned,  an  interruption  in  the  rhythm  of 
discharge  from  the  respiratory  center.  The  inspiratory  muscles, 

"Rosenthal  in  Hermann's  Hanctbuch  cter  PkysioL,  Vol.  IV,  2,  1882. 

17  Pfliiger,  Pfliiger' s  Archiv,  I,  p.  61,  1868. 

13  Traube,  Allgem.  Med.  Centralzeitung,  1862,  No.  38,  and  1863,  No.  97. 


12  RESPIRATION 

and  specially  the  diaphragm,  are,  and  remain  till  the  interruption 
is  broken  by  an  inspiratory  effort,  relaxed.  This  interruption  of 
inspiratory  effort  came  to  be  interpreted  as  an  apnoea,  and  appears 
so  if  only  inspiratory  muscular  movements  are  recorded,  as,  for 
instance,  with  the  method  adopted  in  Hering's  laboratory  by 
Head,19  in  which  only  the  contractions  of  the  diaphragm  are  re- 
corded, or  with  other  methods  which  do  not  record  tonic  expira- 
tory effort.  Hence  it  came  to  be  assumed  that  there  exists  what  is 
called  "vagus  apnoea."  The  next  step  was  to  maintain  that  all 
apnoea  is  in  reality  vagus  apnoea,  and  this  inference  was  supported 
by  the  fact  that  "apnoea"  can  still  be  obtained  when  the  arterial 
blood  is  blue  owing  to  air  containing  a  very  low  percentage  of 
oxygen  being  breathed,  and  can  also  be  produced  (as  Lorrain 
Smith  and  I  found)  by  air  very  rich  in  CO2.  It  was  also  affirmed 
by  Brown-Sequard  that  after  the  vagi  are  cut  apnoea  cannot  be 
produced,  though  this  statement  can  easily  be  shown  to  be  com- 
pletely mistaken.  With  an  efficient  apparatus  for  increasing  the 
ventilation  of  the  lungs  apnoea  can  quite  readily  be  produced 
after  section  of  the  vagi. 

On  the  other  hand,  increasingly  clear  evidence  accumulated 
that  apnoea  due  to  over- ventilation  of  the  blood  passing  through 
the  lungs  exists  as  a  matter  of  fact.  The  most  striking  proof  of 
this  was  afforded  by  experiments  in  which  Fredericq20  crossed 
the  circulation  of  two  animals  by  connecting  the  vessels  in  such  a 
way  that  the  respiratory  center  of  each  animal  was  supplied  with 
arterial  blood  from  the  other  animal.  He  then  found  that  when 
excessive  artificial  respiration  was  produced  in  one  of  the  animals 
apnoea  was  produced  in  the  other,  and  when  the  artificial  respira- 
tion ceased  hyperpnoea  continued  in  the  animal  which  had  had 
artificial  respiration,  since  its  respiratory  center  was  now  receiving 
blood  which  was  venous  owing  to  the  cessation  of  breathing  in  the 
other  animal.  This  hyperpnoea,  on  the  other  hand,  maintained 
the  apnoea  in  the  other  animal,  so  that  one  of  the  animals  re- 
mained apnoeic  while  the  other  remained  hyperpnoeic. 

This  experiment  showed  clearly  the  existence  of  a  true  "chemi- 
cal" apnoea;  but,  as  the  existence  of  vagus  apnoea  was  also  con- 
sidered to  be  firmly  established,  the  existence  of  both  forms  of 
apnoea  came  to  be  generally  assumed.  As  regards  vagus  apnoea  the 
evidence  was  considered  to  show  that  when  apnoea  is  produced  by 
distending  the  lungs  with  air  or  hydrogen  it  is  vagus  apnoea  that 

19  Head,  Journ.  of  Physiol.,  X,  i  and  279,  1889. 
M  Fredericq,  Arch,  der  Physiol.,  17,  p.  563,  1901. 


RESPIRATION  13 

lasts  on  after  the  distention  ceases,  and  from  this  supposed  fact 
the  further  inference  was  drawn  that  repeated  distention  of  the 
lungs  produces  a  summed  vagus  effect  resulting  in  vagus  aprioea 
after  the  distentions  have  ceased.  Thus  the  same  procedure  that 
causes  chemical  apnoea  seemed  to  produce  also  vagus  apnoea, 
and  the  two  kinds  of  apnoea  could  hardly  be  distinguished  in 
practice.  Moreover  hyperpnoea  due  to  any  chemical  cause  such  as 
want  of  oxygen  or  excess  of  CO2  must  apparently  tend  to  be 
prevented  by  the  production  of  vagus  apnoea  due  to  repeated 
distentions  of  the  lungs.  The  two  processes  by  which  the  breathing 
appeared  to  be  regulated  acted,  therefore,  in  opposite  directions. 

As  regards  the  chemical  stimuli  acting  on  the  respiratory  center, 
it  remains  to  consider  the  further  evidence  as  to  the  relative  im- 
portance of  want  of  oxygen  and  excess  of  CO2 ;  also  whether  other 
chemical  stimuli  act  on  the  center.  In  1885  Miescher21  showed 
by  experiments  on  man  that  a  given  small  increase  in  the  per- 
centage of  CO2  in  air  affects  the  breathing  considerably,  while  a 
corresponding  diminution  in  the  oxygen  percentage  has  no  such 
effect.  He  was  thus  led  to  the  conclusion  that  it  is  the  CO2  per- 
centage in  the  air  of  the  lungs  that  ordinarily  determines  the 
chemical  regulation  of  breathing,  and  not  the  oxygen  percentage. 
Thus  CO2  protects  the  body  from  want  of  oxygen  so  long  as 
ordinary  air  is  breathed.  It  will  be  seen  in  the  sequel  how  rela- 
tively correct  this  general  view  of  Miescher's  was,  although  he 
maintained  the  existence  of  vagus  apnoea  and  thus  shared  in  the 
mistakes  of  his  time. 

In  1888  Geppert  and  Zuntz22  published  the  results  of  a  very 
careful  series  of  experiments  on  the  effects  of  muscular  work  (pro- 
duced by  tetanizing  the  hind  limbs  of  an  animal  after  section  of  the 
spinal  cord)  on  respiration.  After  bringing  forward  new  evidence 
that  it  is  the  blood  which  carries  the  stimulus  for  increased  breath- 
ing to  the  respiratory  center  they  showed  that  during  the  work 
the  proportion  of  CO2  in  the  blood  was  greatly  diminished,  and 
that  there  was  also  a  slight  increase  in  the  oxygen  percentage  of 
the  blood.  Hence,  they  argued,  it  is  neither  increase  in  CO2  per- 
centage nor  diminution  in  oxygen  percentage  that  causes  the 
hyperpnoea  accompanying  muscular  exertion.  They  believed  that 
it  is  some  acid  substance  produced  in  the  muscles,  and  pointed  out 
that  Walter  had  found  that  the  breathing  is  much  increased  in 
poisoning  by  acids. 

21  Miescher,  Arch.  f.  (Anat.  uJ)  Physiol.,  p.  355,  1885. 

32  Geppert  and  Zuntz,  Pfltiger's  Archiv,  XLII,  pp.  195,  209,  1888. 


I4  RESPIRATION 

From  the  foregoing  review  of  the  knowledge  existing  up  to 
the  beginning  of  the  present  century  on  the  physiological  regu- 
lation of  breathing  it  will  be  seen  that  the  conclusions  reached 
were  unsatisfactory  in  many  ways,  and  to  some  extent  contra- 
dictory. On  the  one  hand  the  nervous  regulation  through  the  vagi 
and  other  nerves  seemed  to  have  no  relation  to  the  requirements 
of  the  body  for  oxygen  and  for  removal  of  CO2,  and  in  fact  to 
act  antagonistically  to  these  requirements.  On  the  other  hand 
the  excitation  of  the  breathing  during  muscular  work  seemed 
also,  from  the  results  of  Geppert  and  Zuntz,  to  have  no  definite 
relation  to  increased  requirements  for  oxygen  and  CO2.  There 
was  also  no  definite  quantitative  information  as  to  why  in  normal 
breathing  during  rest  the  composition  of  the  expired  air  is  so 
constant  as  it  is.  Without  more  exact  and  consistent  physiological 
knowledge  it  appeared  to  be  very  difficult  to  interpret  the  ab- 
normal breathing  so  often  met  with  in  disease,  or  to  know  how  to 
set  about  investigating  it. 

From  still  another  standpoint  the  existing  knowledge  was  very 
unsatisfactory  to  me  personally.  From  a  consideration  of  the 
general  characteristics  which  distinguish  a  living  organism  from 
a  machine  I  had  become  convinced  that  a  living  organism  cannot 
be  correctly  studied  piece  by  piece  separately  as  the  parts  of  a 
machine  can  be  studied,  the  working  of  the  whole  machine  being 
deduced  synthetically  from  the  separate  study  of  each  of  the  parts. 
A  living  organism  is  constantly  showing  itself  to  be  a  self-main- 
taining whole,  and  each  part  must  therefore  always  be  behaving 
as  a  part  of  such  a  self-maintaining  whole.  In  the  existing 
knowledge  of  the  physiology  of  breathing  this  characteristic  could 
not  be  clearly  traced.  The  regulation  of  breathing  did  not,  as 
represented  in  the  existing  theories,  appear  to  be  determined  in 
accordance  with  the  requirements  of  the  body  as  a  whole;  and 
for  this  reason  I  doubted  the  correctness  of  these  theories,  and 
suspected  that  errors  had  arisen  through  the  mistake  of  not  study- 
ing the  breathing  as  one  of  the  coordinated  activities  of  the  whole 
body.  In  so  far  as  the  investigations  detailed  in  succeeding  chap- 
ters originated  with  me,  they  were  mainly  inspired  by  the  con- 
siderations just  mentioned;  and,  as  will  be  seen  in  the  sequel,  the 
same  considerations  have  led  to  a  reinvestigation  and  reinterpre- 
tation  of  other  physiological  activities  besides  breathing. 


CHAPTER  II 
Carbon  Dioxide  and  Regulation  of  Breathing. 

MY  attention  was  first  directed  to  the  regulation  of  breathing  by 
a  series  of  experiments  carried  out  by  Lorrain  Smith  and  myself1 
as  to  the  question  whether,  as  had  shortly  before  been  asserted  by 
Brown-Sequard  and  d'Arsonval  as  a  result  of  a  very  definite  and 
apparently  convincing  series  of  experiments,  a  poisonous  organic 
substance  is  given  off  in  expired  air.  The  results  of  our  experi- 
ments, which  were  made  partly  on  man  and  partly  on  animals, 
were  entirely  negative,  and  left  no  doubt  in  our  minds  that  the 
apparent  positive  results  described  were  due  partly  to  undetected 
air  leaks  which  led  to  animals  being  asphyxiated,  and  partly  to 
other  experimental  errors.  In  the  human  experiments  we  used  an 
air-tight  respiration  chamber  of  about  70  cubic  feet  capacity,  in 
which  the  air  became  more  and  more  vitiated  by  respiration. 

The  effects  of  the  vitiated  air  on  our  breathing  attracted  our 
attention  specially.  When  the  proportion  of  CO2  in  the  air  rose 
to  about  3  per  cent,  and  the  oxygen  fell  to  about  1 7  per  cent  (there 
being  20.94  per  cent  of  oxygen  and  0.03  per  cent  of  CO2  in  pure 
atmospheric  air)  the  breathing  began  to  be  noticeably  increased. 
With  further  vitiation  the  increase  in  breathing  became  more  and 
more  marked,  until  with  about  6  per  cent  of  CO2  and  13  per  cent 
of  oxygen  the  panting  was  very  great,  with  much  consequent 
exhaustion. 

When  the  experiment  was  repeated,  with  the  difference  that 
the  CO2  was  absorbed  by  means  of  soda  lime,  there  was  no  notice- 
able increase  in  the  breathing  before  the  oxygen  fell  below  about 
14  per  cent.  When,  finally,  the  CO2  was  left  in  the  air,  but  oxygen 
was  first  added  so  that  the  oxygen  remained  abnormally  high 
throughout,  the  panting  was  just  the  same  as  when  ordinary  air 
was  used.  In  short  experiments  in  which  the  same  air  was 
rebreathed  from  a  large  bag  till  we  could  no  longer  stand  the 
experiment  we  found  that  we  had  to  stop  at  about  10  per  cent  of 
CO2,  whether  oxygen  was  added  or  not,  and  that  the  oxygen  per- 
centage made  no  difference  to  the  distress  produced.  In  these 
experiments  there  was  only  about  8  to  9  per  cent  of  oxygen  in  the 

1  Haldane  and  Lorrain  Smith,  Journal  of  Pathology  and  Bacteriology,  I,  pp. 
168  and  318,  1893. 


1 6  RESPIRATION 

rebreathed  air  at  the  end  of  the  experiment;  but  even  this  made 
no  difference  to  the  breathing.  When,  on  the  other  hand,  a  mixture 
containing  a  greatly  reduced  oxygen  percentage,  without  any 
addition  of  CO2,  was  breathed,  the  breathing  was  increased  sensi- 
bly, as  shown  by  graphic  records,  when  the  oxygen  fell  to  about 
12  per  cent,  and  was  greatly  increased  by  lower  percentages. 
With  extremely  low  percentages,  such  as  2  per  cent,  consciousness 
was  lost  quite  suddenly  after  about  50  seconds,  before  there  was 
time  to  notice  any  increase  in  the  breathing. 

It  was  evident  from  these  experiments  that  when  the  same  air 
is  rebreathed,  or  an  insufficient  proportion  of  fresh  air  is  supplied, 
the  increased  breathing  produced  is  due  simply  to  excess  of  CO2, 
until,  at  least,  the  oxygen  percentage  becomes  extremely  low.  It 
appeared,  therefore,  that  the  variations  in  ordinary  breathing  in 
response  to  variations  in  the  respiratory  exchange  must  be  due 
to  the  increased  CO2  produced,  and  not  to  the  increased  consump- 
tion of  oxygen.  This  conclusion  was  the  same  as  that  of  Miescher, 
and  supported  his  views  as  to  the  regulation  of  respiration. 

When  more  than  about  10  per  cent  of  CO2  was  breathed  the 
effect  of  the  mixture  was  to  produce  stupefaction,  which  was  very 
marked  with  higher  percentages.  This  effect  was  already  well 
known  in  animals,  and  CO2  was  one  of  the  gases  tried  as  an  an- 
aesthetic by  Sir  James  Simpson  before  he  adopted  chloroform. 
The  effect  of  excess  of  CO2  in  producing  ataxia,  stupefaction,  and 
loss  of  consciousness  has  become  very  familiar  to  me  in  connection 
with  experiments  with  mine-rescue  apparatus  and  diving  appa- 
ratus. These  effects  are  readily  produced  in  the  presence  of  a  large 
excess  of  oxygen,  and  are  therefore  quite  independent  of  the 
effects  of  want  of  oxygen.  The  narcotic  effect  of  a  large  excess  of 
CO2  quiets  down  the  respiration,  and  this  effect  in  animals  led 
many  previous  observers  to  overlook  almost  entirely  the  ordinary 
effects  of  CO2  in  stimulating  the  breathing. 

During  the  next  few  years  after  our  first  experiments  I  was 
engaged  in  the  investigation  of  other  problems  connected  with 
general  metabolism,  respiration,  and  blood  gases,  but  in  1903 
returned  to  the  regulation  of  breathing  in  a  long  series  of  experi- 
ments carried  out  in  conjunction  with  Dr.  J.  G.  Priestley,  who 
was  then  a  student  at  Oxford. 

It  seemed  pretty  evident  that  in  order  to  reach  clear  ideas  on 
the  regulation  of  breathing  it  was  necessary  to  study  very  care- 
fully the  composition  of  the  alveolar  air  which  is  in  contact, 
through  the  alveolar  epithelium,  with  the  blood  passing  through 


RESPIRATION  17 

the  lungs ;  also  that  this  could  be  best  done  on  man.  The  composi- 
tion of  human  alveolar  air  under  different  conditions  had  already 
been  calculated  by  Loewy2  and  Zuntz  from  the  volume  occupied 
by  a  plaster  cast  of  the  respiratory  passages  in  a  dead  body  and 
the  average  composition  and  volume  of  a  breath  of  expired  air. 
The  expired  air  is  evidently  a  mixture  of  air  from  the  alveoli  with 
the  air  which  remains  in  the  respiratory  tubes  at  the  end  of  inspira- 
tion. This  air  is  presumably  but  little  altered  by  diffusion  through 
the  walls  of  the  respiratory  tubes,  and  so  far  as  respiratory  ex- 
change is  concerned  the  volume  of  the  lumen  of  these  tubes  must 
constitute  a  "dead  space"  in  breathing.  The  dead  space  is  occupied 
by  alveolar  air  at  the  end  of  expiration,  and  by  more  or  less  pure 
atmospheric  air  at  the  end  of  inspiration. 

If  we  know  the  volume  of  the  dead  space,  and  the  volume  and 
composition  of  the  air  expired  at  each  breath,  we  can  calculate 
the  average  composition  of  the  alveolar  air.  It  is,  however,  im- 
possible to  estimate  directly  the  volume  of  the  dead  space  in  a 
particular  individual  with  any  accuracy,  or  to  be  sure  that  it 
remains  the  same  under  different  physiological  conditions.  The 
bronchi  and  bronchioles  are  provided  with  a  muscular  coat  by 
means  of  which  their  lumen  is  capable  of  contracting  or  dilating. 
Apart  from  this  the  air  in  the  alveoli  which  are  nearest  to  the  end 
of  a  bronchus  will  contain  purer  air  during  inspiration  than  during 
expiration,  and  this  introduces  a  further  complication. 

To  get  a  reliable  knowledge  of  the  composition  of  alveolar  air 
it  seemed  desirable  to  make  direct  determinations.  The  method 
introduced  by  Priestley  and  myself3  is  simply  to  make  a  sharp  and 
deep  expiration  through  a  piece  of  hose  pipe  about  four  feet  long 
and  one  inch  in  diameter,  and  provided  with  a  plain  glass  mouth- 
piece which  is  closed  by  the  tongue  at  the  end  of  the  expiration 
(Figure  i).  By  means  of  a  narrow  bore  glass  tube  filled  with 
mercury  and  introduced  air-tight  into  the  hose  pipe  near  the 
mouthpiece,  a  sample  of  the  last  part  of  the  expired  air  is  then 
at  once  taken  directly  into  the  gas  analysis  apparatus  as  indicated 
in  Figure  i,4  or  else  into  a  vacuous  sampling  tube.5  If  the  sample 
is  to  be  a  normal  one  the  breathing  must  be  quite  normal  before 

2  Loewy,  Pfluger's  Archiv,  LVIII,  p.  416,   1894. 

8  Haldane  and  Priestley,  Journ.  of  Pkysiol.,  XXXII,  p.  225,  1905. 

*  For  physiological  work  methods  of  air  analysis  which  are  both  accurate  and 
rapid  are  required.  A  description  of  the  methods  which  I  introduced  with  this  in 
view  will  be  found  in  my  book,  Methods  of  Air  Analysis,  London,  Charles  Griffin 
&  Co.,  Third  Edition,  1920. 

*  If  the  sample  is  too  large  some  pure  air  may  be  drawn  in. 


18 


RESPIRATION 


the  deep  expiration ;  and  it  requires  some  care  to  secure  this.  Under 
normal  resting  conditions  the  depth  of  expiration  needed  in  order 
to  give  a  reliable  sample  at  the  end  of  inspiration  is  at  least  800  cc. 
With  less  than  this  the  sample  is  likely  to  be  mixed  with  air  of 


Figure  i. 
Apparatus  for  obtaining  and  analysing  alveolar  air. 

the  apparent  dead  space;  for  though  with  normal  breathing  the 
volume  of  the  apparent  dead  space  is  far  less  than  800  cc.,  at  least 
three  or  four  times  its  volume  of  alveolar  air  is  needed  in  order 
to  flush  it  and  the  breathing  tube  out  thoroughly.  If  more  than 
about  800  cc.  are  expired,  the  composition  of  the  sample  is  the 
same  whatever  the  depth  of  the  expiration,  and  we  designated 
air  of  this  constant  composition  as  "alveolar  air"  although,  as 
will  be  shown  later,  the  composition  of  the  air  in  the  alveoli  is  by 
no  means  such  a  simple  matter  as  we  thought.  The  following  are 
the  averages  of  results  which  I  obtained  on  this  point  when  the 
samples  were  taken  just  at  the  end  of  inspiration.6 


Vol.  of  air  expired 
through  tube 

190  cc. 

335 
5io 
650 
950 
1350 


Per  cent  of  COz  in  sample 
taken  from  tube 

3-03 

4-37 
5-04 
5-19 

5-51 
5.48 


As  soon  as  this  method  of  sampling  the  alveolar  air  was  applied 
on  ourselves  and  others  it  became  evident  that  the  alveolar  CO2 
and  O2  percentage  during  rest  under  normal  conditions  are  sur- 

*  Haldane,  Amer.  Journ.  of  Physiol.,  XXXVIII,  p.  20,  1915. 


RESPIRATION  19 

prisingly  constant  for  each  individual.  As  the  depth  of  breathing 
cannot  be  kept  absolutely  steady  and  the  composition  of  the  al- 
veolar air  varies  slightly  with  inspiration  and  expiration  it  is 
best  to  take  at  least  two  samples — one  just  at  the  end  of  inspiration, 
and  another  just  at  the  end  of  expiration.  The  following  tables 
give  the  CO2  percentages  in  samples  of  our  normal  resting 
alveolar  air,  taken  in  the  sitting  position  during  rest  at  intervals 
over  about  20  months  in  1903  to  1905.  Since  then  we  have  made 
many  further  determinations,  but  the  percentages  have  remained 
nearly  the  same.  They  are  slightly  lower  or  higher  on  some  days 
than  on  others,  and  other  observers  have  noticed  this  in  them- 
selves. 


J. 

S.  H. 

Barometric 

COi  per  cent, 

CO*  per  cent. 

COa  per  cent, 

pressure  in 

end-  of 

end  of 

mean 

mm.  of  Hg. 

inspiration 

expiration 

759 

5-33 

5.76 

5-545 

747 

5-47 

5.69 

5.56 

748 

5.56 

5-70 

5.63 

748 

5-59 

5.87 

573 

748 

5-38 

5.60 

5-49 

748 

5-33 

5-94 

5-40 

749 

5-8o 

5-5i 

5-87 

749 

5-66 

5-59 

5.585 

765 

5.63 

5.83 

5.6i 

759 

5-42 

5-72 

5-625 

758       . 

5-74 

5-72 

571 

765 

5-53 

5-72 

5-62 

Mean  754 

5-54 

5-72 

5-63 

It  will  be  seen  that,  as  might  be  expected,  the  inspiratory 
samples  give  on  an  average  a  somewhat  lower  result  than  the 
expiratory  ones.  The  average  for  one  subject  is  5.63  per  cent  and 
for  the  other  6.28.  The  slight  variations  of  individual  results 
from  these  averages  are  evidently  not  due  merely  to  changes  in 
barometric  pressure. 

When  ordinary  air  was  breathed  the  oxygen  percentage  in  the 
alveolar  air  was  nearly  as  steady  as  the  CO2  percentage.  When, 
however,  the  oxygen  and  CO2  percentages  in  the  inspired  air 
were  varied  it  became  quite  evident  that  the  breathing  is  regu- 


20 


RESPIRATION 


J. 

G.  P. 

Barometric 

COa  per  cent, 

COz  per  cent, 

COt  per  cent, 

pressure  in 

end,  of 

end,  of 

mean 

mm.  of  ffg. 

inspiration 

expiration 

759 

6.18 

6-43 

6.305 

754 

6.5I 

6.63 

6.57 

747 

6.10 

6.70 

6.40 

753 

6.81 

6.86 

6.835 

758 

5-95 

6.74 

6-35 

758 

5-82 

6.23 

6.025 

758 

5-93 

6.21 

6.07 

754 

6.12 

6.33 

6.215 

754 

6.26 

6.20 

6.23 

754 

6.23 

6.05 

6.14 

75i 

5-66 

6.75 

6.205 

75i 

5.98 

5-99 

5.985 

762 

6.37 

6.29 

6.33 

762 

6.24 

6.09 

6.165 

765 

6-39 

6.43 

6.41 

Mean  756 

6.17 

6-39 

6.28 

lated  so  as  to  give  a  constant  percentage  of  CO2  and  not  of  oxy- 
gen. The  following  results  were  obtained  with  oxygen  percentages 
varied  at  intervals  in  the  same  subject. 


OXYGEN 

PERCENTAGE 

CO2 

PERCENTAGE 

Inspired,  at 

r          Alveolar  air 

Inspired, 

air          Alveolar  air 

80.24 

72.21 

0.20 

5.84 

63.67 

57-57 

0.14 

5.41 

20.93 

14.50 

0.03 

5-54 

16.03 

10.39 

O.O5 

5-62 

15.82 

10.59 

0.05 

5.6o 

15.63 

10.60 

0.07 

5-45 

12.85 

8-34 

0.06 

5.37 

12.78 

7.80 

0.07 

5.28 

11-33 

8.96 

O.IO 

3.85 

11.09 

7.10 

0.10 

4-89 

6.23 

4.30 

0.09 

3-57 

This  table  shows  that  increase  in  the  oxygen  percentage  over 
short  periods  had  no  noticeable  influence  on  the  alveolar  CO2 
percentage,  and  that  not  until  the  oxygen  percentage  in  the  in- 


RESPIRATION  21 

spired  air  was  lowered  to  about  12  or  13  and  the  alveolar  oxygen 
percentage  to  about  8  was  there  any  marked  decrease  in  the  CO2 
percentage.  With  a  greater  lowering  of  the  oxygen  percentage 
than  this,  however,  the  breathing  was  so  much  increased  as  to 
lower  the  CO2  percentage  considerably. 

When  the  CO2  percentage  in  the  inspired  air  was  increased, 
on  the  other  hand,  the  effect  was  strikingly  different.  Instead  of 
the  alveolar  CO2  rising  in  any  direct  correspondence  to  the  rise 
in  the  inspired  CO2,  the  increase  in  alveolar  CO2  was  so  slight  as 
to  be  hardly  appreciable  even  with  a  rise  of  2  or  3  per  cent  in  the 
CO2  of  the  inspired  air.  This  is  evident  from  the  following  ex- 
periments, made  in  the  air-tight  chamber. 


SUBJECT  CO2  PER  CENT                 CO2  PER  CENT  IN      RELATIVE 
IN  INSPIRED                     ALVEOLAR  AIR       RATES  OF 
AIR                                                                     ALVEOLAR 
VENTILATION 

End  of 

End  of 

inspiration 

expiration 

Mean 

J.  S.  H.               0.03 

5-42 

5-83 

5.62 

IOO 

2.07 

5.60 

— 

— 

153 

3-80 

6.03 

5-92 

5-97 

258 

0.03 

5-74 

5-72 

5-71 

IOO 

1.74 

5-59 

5.71 

5.65 

143 

3.98 

5-99 

6.16 

6.03 

277 

5.28 

6.44 

6.66 

6-55 

447 

J.  G.  P.              0.03 

6-85 

6.28 

6.31 

IOO 

5-29 

6.92 

6.86 

6.89 

392 

6.66 

7.62 

7.72 

7.67 

622 

7.66 

8.34 

8.56 

8-45 

795 

The  evident  effect  of  adding  CO2  to  the  inspired  air  was  so  to 
increase  the  breathing  that,  if  the  percentage  added  was  not  too 
high,  the  CO2  percentage  in  the  alveolar  air  was  kept  nearly 
constant.  Of  the  delicacy  of  this  reaction  it  is  easy,  from  the  fig- 
ures, to  form  a  fair  estimate.  With  a  moderate  amount  of  hyperp- 
noea,  and  provided  that,  as  was  actually  the  case,  sufficient  time 
has  elapsed  to  eliminate  the  influence  of  any  temporary  damming 
back  of  CO2  within  the  body,  the  discharge  of  CO2  by  the  lungs 
is  about  the  same  during  hyperpnoea  as  during  rest.  Hence  it 
is  possible  to  calculate  how  great  a  relative  increase  in  the  alve- 
olar ventilation  is  brought  about  by  a  given  increase  in  the  alveolar 


22  RESPIRATION 

CO 2  percentage.  We  found  that  about  0.23  per  cent  increase  in 
the  alveolar  CO2  gives  100  per  cent  increase  in  the  resting  alveolar 
ventilation.  For  instance  with  4.16  per  cent  of  CO2  in  the  inspired 
air,  the  alveolar  CO2  percentage  would  rise  to  about  6.06  per 
cent,  if  it  had  been  about  5.6  per  cent  when  pure  air  was  breathed. 
As  the  difference  between  4.16  and  6.06  is  only  a  third  of  the 
difference  between  o.o  and  5.6,  it  follows  that  the  alveolar  ventila- 
tion is  thrice  as  great  with  the  slightly  raised  alveolar  CO2  per- 
centage. 

A  more  precise  measure  of  the  effects  of  raising  the  alveolar 
CO2  percentage  on  the  lung  ventilation  has  more  recently  been 
obtained  by  Campbell,  Douglas,  and  Hobson,7  who  found  that  for 
an  increase  of  10  liters  per  minute  in  the  volume  of  air  breathed 
there  was  an  increase  of  0.28  per  cent  (or  2  mm.  of  mercury 
pressure)  in  the  alveolar  CO2.  An  increase  of  0.17  per  cent  was 
sufficient  to  double  the  alveolar  ventilation  during  complete  rest 
in  a  deck  chair. 

If  an  increase  of  0.2  per  cent  in  the  alveolar  CO2  is  sufficient 
to  double  the  alveolar  ventilation  it  might  be  expected  that  a 
decrease  of  0.2  per  cent  would  cause  the  breathing  to  cease.  As 
already  mentioned,  forced  breathing  or  excessive  artificial  respira- 
tion causes  temporary  cessation  of  natural  breathing,  or  apnoea. 
After  forced  breathing  for  about  a  minute  the  subsequent  apnoea 
commonly  lasts  for  about  1^2  minutes  in  man.  The  alveolar  CO2 
percentage  is  markedly  diminished  for  a  few  seconds  by  even  a 
single  extra  deep  breath  of  pure  air,  and  correspondingly  in- 
creased by  a  breath  of  air  containing  more  than  5  or  6  per  cent  of 
CO2.  It  is  easy  to  show,  however,  that  the  full  effect  of  the  dimin- 
ished or  increased  percentage  of  CO2  on  the  respiratory  center  is 
not  immediate.  This  is  just  what  might  be  expected.  The  arterial 
blood  leaving  the  lungs  at  any  moment  is  doubtless  saturated  with 
CO2  to  a  point  corresponding  with  the  existing  percentage  of  CO2 
in  the  alveolar  air;  but  when  this  blood  reaches  the  tissues  it 
comes  in  contact  with  tissue  and  lymph  saturated  with  CO2  to  the 
normal  extent,  but  possessing  a  considerable  capacity  for  absorbing 
more  CO2.  In  consequence  of  this  the  tissues,  including  the  res- 
piratory center,  take  some  time  to  get  into  equilibrium  with  the 
new  level  of  saturation  with  CO2  in  the  arterial  blood.  Hence  in 
order  to  measure  the  real  effect  of  any  increase  or  diminution  in 
the  alveolar  CO2  percentage,  it  is  necessary  to  maintain  this  per- 
centage constant  for  some  time.  When  air  containing  an  excess 

'Campbell,  Douglas,  and  Hobson,  Journ.  of  Physiol.,  XLVIII,  p.  303,   1914. 


RESPIRATION  23 

of  CO2  is  breathed,  the  alveolar  CO2  percentage  naturally  be- 
comes constant  after  a  few  minutes ;  but  with  forced  breathing  of 
ordinary  air  it  is  not  possible  to  maintain  an  alveolar  CO2  per- 
centage which  is  below  the  normal  by  some  required  small  amount. 

To  get  over  this  difficulty  we  employed  forced  breathing  with 
air  to  which  CO2  had  been  added,  and  found  that  on  successive 
trials  with  increasing  percentages  of  CO2  in  the  inspired  air 
the  duration  of  apnoea  following  forced  breathing  diminished 
until,  when  there  was  more  than  about  4.7  per  cent  of  CO2  in  the 
inspired  air,  no  apnoea  at  all  was  produced.  It  was  thus  evident 
that  a  very  small  diminution  in  the  alveolar  CO2  percentage 
produces  apnoea.  The  actual  composition  of  the  alveolar  air  at  the 
end  of  forced  breathing  in  similar  experiments  was  determined 
later  by  Douglas  and  myself.8  It  was  found  that  with  more  than 
4.7  per  cent  of  CO2  in  the  inspired  air  no  apnoea  could  be  produced 
by  forced  breathing,  however  hard,  in  a  person  whose  normal 
alveolar  CO2  percentage  was  about  5.6,  and  that  apnoea  was  only 
produced  if  the  alveolar  CO2  was  reduced  by  more  than  0.2  per 
cent  below  the  normal.  When,  however,  the  CO2  in  the  inspired 
air  was  lower,  so  that  the  alveolar  CO2  percentage  was  reduced 
by  more  than  0.2  per  cent,  apnoea  was  produced. 

It  is  thus  clear  that  the  cause  of  the  apnoea  following  forced 
breathing  is  reduction  in  the  CO2  percentage  in  the  alveolar  air, 
and  that  a  reduction  of  as  little  as  0.2  per  cent  is  sufficient  to  cause 
apnoea.  The  astounding  sensitiveness  of  the  respiratory  center  to 
CO2  is  thus  clearly  established  in  both  an  upward  and  a  downward 
direction.  A  mean  increase  or  diminution  of  .01  per  cent  in  the 
alveolar  CO2  will  evidently  produce  an  increase  or  diminution  of 
5  per  cent  in  the  alveolar  ventilation,  or  of  about  400  cc.  per  minute 
in  the  lung  ventilation. 

It  may  be  useful  to  review  briefly  the  sources  of  error  in  the 
views  current  until  recently  with  regard  to  the  causes  of  the  apnoea 
produced  by  excessive  ventilation  of  the  lungs.  One  view  was 
that  the  excess  of  oxygen  in  the  arterial  blood  causes  the  apnoea. 
This  theory  had  so  little  evidence  to  support  it  that  it  is  very 
surprising  that  it  should  have  remained  current  so  long.  It  is 
true  that  during  excessive  artificial  respiration  the  arterial  blood 
contains  slightly  more  oxj^gen  than  usual;  but  there  is  a  still 
greater  excess  during  the  quiet  normal  breathing  of  pure  oxygen, 
which  causes  not  the  smallest  sign  of  apnoea.  Rosenthal9  laid  great 

8  Campbell,  Douglas,  Haldane,  and  Hobson,  Journ.  of  Physiol,,  XLVI,  p.  312. 
- 
Rosenthal  in  Hermann's  Handbuch  tier  Physiologic,  IV,  2,  p.  266. 


24  RESPIRATION 

stress  on  an  experiment  in  which  on  slightly  raising  the  pres- 
sure in  a  spirometer  from  which  an  animal  is  breathing,  the  an- 
imal stops  breathing;  and  he  attributed  this  to  increase  in  the 
partial  pressure  of  the  oxygen  in  the  spirometer.  The  real  cause 
was  quite  evidently  the  distention  of  the  animal's  lungs  by  the 
pressure,  as  in  the  experiments  of  Hering  and  Breuer.  When  a 
man  or  animal  has  been  rendered  hyperpnoeic  from  want  of  oxy- 
gen, and  the  hyperpnoea  has  reduced  the  normal  percentage  of 
CO2  in  the  alveolar  air  and  blood,  apnoea  is  produced  by  supply- 
ing more  oxygen;  but  this  apnoea  is  of  course  dependent  on  de- 
ficiency of  CO2,  and  cannot,  therefore,  be  cited  in  support  of  the 
oxygen  theory  of  ordinary  apnoea. 

The  other  erroneous  theory — that  apnoea  following  forced 
breathing  is  due  to  a  summation  of  inhibitory  vagus  stimuli  aris- 
ing from  distention  of  the  lungs  in  the  forced  breathing — 
was  based  on  two  fallacies.  The  first  was  that  intact  vagi  are 
necessary  for  the  production  of  apnoea  by  artificial  respira- 
tion. This  is  certainly  not  the  case;  for  apnoea  can  be  produced 
quite  promptly  and  easily  after  section  of  the  vagi.  It  is  necessary, 
however,  to  make  sure  that  the  excessive  artificial  ventilation  is 
really  effective  in  ventilating  the  lungs,  since  after  section  of  the 
vagi  the  natural  breathing  does  not  follow  the  rhythm  of  the 
artificial  respiration,  and  may  thus  partly  annul  the  effects  of 
the  latter. 

The  other  fallacy  connected  with  the  vagus  theory  of  ordinary 
apnoea  was  that  when  air  containing  little  or  no  oxygen  is  used 
for  artificial  respiration  an  apnoea  due  to  excessive  aeration  of 
the  blood  is  impossible.  Advocates  of  the  vagus  theory  wrongly 
thought  only  of  oxygen  want  in  connection  with  aeration  of  the 
blood.  They  thus  attributed  to  vagus  excitation  any  apnoea  which 
was  produced  in  presence  of  defective  oxygenation  of  the  blood, 
ignoring  the  fact  that  deficiency  of  CO2  was  present  along  with 
defective  oxygenation,  and  that  this  fact  explained  the  observed 
apnoea.  Provided  that  the  alveolar  CO2  percentage  is  sufficiently 
reduced,  apnoea  can  be  produced  readily  in  spite  of  great  defi- 
ciency of  oxygen  in  the  alveolar  air. 

The  fact  that  apnoea  is  produced  when  forced  breathing  reduces 
the  alveolar  CO2  percentage  by  as  little  as  0.2  per  cent  (with  the 
alveolar  oxygen  percentage  not  abnormally  low),  and  that  if  this 
reduction  is  prevented  no  amount  of  excessive  lung  ventilation 
will  produce  apnoea,  affords,  in  conjunction  with  the  other  facts 
already  referred  to,  conclusive  evidence  that  the  apnoea  following 


RESPIRATION  25 

excessive  lung  ventilation  is  due  to  lowering  of  the  alveolar  CO2 
percentage,  and  not  to  either  of  the  other  causes  to  which  the 
apnoea  has  also  been  attributed.  The  vagus  theory  of  the  apnoea 
caused  by  increased  lung  ventilation  involved  the  very  great 
improbability  that  a  special  arrangement  exists  in  the  body  for 
bringing  increased  breathing  to  an  end,  regardless  of  whether  a 
continuance  of  the  increased  breathing  is  physiologically  required 
or  not.  It  seemed  almost  incredible  that  such  a  theory  could  be 
correct. 

The  ease  with  which  apnoea  due  to  reduction  of  CO2  in  the 
alveolar  air  might  be  taken  for  an  apnoea  due  to  the  after  effect 
of  mere  distention  of  the  lungs  is  clearly  shown  by  the  stetho- 
graphic  tracings  of  human  breathings  reproduced  in  Figures  2 
to  7.10  Figure  2  shows  apnoea  as  an  after  effect  of  inflation  of  the 
lungs,  while  Figure  3  shows  that  when  the  inflation  is  made  with 
air  containing  4.6  per  cent  of  CO2,  so  as  to  prevent  reduction  of 
the  alveolar  CO2  percentage,  no  apnoea  succeeds  the  period  of 
inflation.  The  apnoea  appearing  as  an  after  effect  in  Figure  2  is 
therefore  due  to  reduction  of  the  alveolar  CO2  in  consequence  of 
the  distention  with  pure  air. 


Figure  2. 


Figure  3. 

Effects  of  distention  for  8  sees.  Crosses  show  beginning 
and  end  of  distention.  To  read  from  left  to  right.  In  Fig.  2 
pure  air  is  used  for  distention ;  in  Fig.  3  air  containing 
4.62  per  cent  COz. 

Figures  4,  5,  and  6  illustrate  the  same  point.  In  Figures  4  and 
5  there  is  apnoea  succeeding  a  short  distention,  but  not  immedi- 

10  Christiansen  and  Haldane,  Journ.  of  Physwl.,  XLVIII,  p.  274,   1914. 


26 


RESPIRATION 


ately,  since  a  few  seconds  were  needed  before  the  "apnoeic"  blood 
could  affect  the  respiratory  center.  In  Figure  6  the  distention  was 
sufficiently  prolonged  for  the  "apnoeic"  blood  to  affect  the  center 
before  the  end  of  distention.  The  effect  is  therefore  similar  to 
that  in  Figure  2. 


Figure  4. 


Figure  5. 


Figure  6. 

Effects  of  distention  with  pure  air  for  increasing  short 
periods.  Crosses  show  beginning  and  end  of  distention.  To  read 
from  left  to  right.  Fig.  4  distention  for  i  sec. ;  Fig.  5  for  3  sees. ; 
and  Fig.  6  for  5  sees. 


The  regularity  of  ordinary  breathing  is  constantly  being  inter- 
fered with  in  various  ways,  as  for  instance  during  talking  or 
singing;  and  the  breath  can  if  necessary  be  held  for  about  a  minute 
by  voluntary  effort.  The  readiness  with  which  these  interruptions 
occur  has  given  rise  to  the  popular  idea  that  the  supply  of  air  to 
the  lungs  is  to  a  large  extent  under  voluntary  control,  and  can  be 
increased  or  diminished  by  proper  training.  In  reality  the  mean 


RESPIRATION  27 

ventilation  of  the  lungs  is  not  affected  by  ordinary  interruptions. 
This  is  strikingly  shown  by  experiments  which  we  made  on  the 
effects  of  voluntarily  varying  the  frequency  of  breathing. 

The  frequency  of  breathing  varies  considerably  among  normal 
individuals,  or  in  the  same  individual  at  different  times ;  and  it  is 
easy  to  vary  the  frequency  while  leaving  the  depth  of  breathing 
to  regulate  itself  in  a  natural  manner.  On  making  experiments  of 
this  kind  Priestley  and  I  found  the  following  percentages  of  CO2 
in  the  alveolar  air : 


ALVEOLAR  CO2  PERCENTAGE 

RESPIRATIONS 

End,  of 

End  of 

Mean 

PER  MINUTE 

.  inspiration 

expiration 

J.  S.  H. 

9 

5-59 

5.87 

573 

19 

5.56 

570 

5.63 

J.  S.  H. 

9 

5-33 

5-47. 

540 

20 

5-44 

5.60 

5-52 

J.  G.  P. 

10.5 

5-95 

6.74 

6-35 

30 

5.98 

6.05 

6.02 

In  a  recent  series,  made  on  myself  ten  years  later,11  the  fre- 
quency was  varied  within  much  wider  limits,  with  the  following 
results : 


ALVEOLAR  CO2  PERCENTAGE 

RESPIRATIONS 

End  of 

End  of 

Mean 

PER 

MINUTE 

inspiration 

expiration 

{ 

30 

4 

5-66 

5-24 

570 
6.09 

S-te 
5-66 

( 

24 

5.48 

5-49 

5.48 

( 

6 

5-40 

573 

5.56 

r 

36 

5.63 

573 

5-68 

J 

4 

5.II 

6.34 

572 

1 

3 

5-10 

6.24 

5.71 

I 

60 

6.17 

6.16 

6.16 

It  will  be  seen  that  in  spite  of  variations  from  3  to  36  per  minute 
in  the  frequency  of  breathing  the  alveolar  CO2  percentage  re- 

"Haldane,  Amer.  Journ.  of  PhysioL,  XXXVIII,  p.  20,  1915. 


28  RESPIRATION 

mained  constant,  since  increased  or  diminished  depth  of  breathing 
compensated  for  diminished  or  increased  frequency.  The  manner 
in  which  this  correspondence  between  depth  and  frequency  is 
brought  about  will  be  discussed  in  the  next  chapter. 

During  any  considerable  muscular  exertion  the  discharge  of 
CO2  from  the  lungs  is  enormously  increased ;  and  in  view  of  the 
facts  already  described  we  should  expect  to  find  the  breathing 
similarly  increased,  with  a  rise  in  the  alveolar  CO2  percentage 
corresponding  to  the  rise  observed  when  the  breathing  is  corre- 
spondingly increased  by  breathing  air  containing  an  excess  of 
CO2.  Priestley  and  I  obtained  the  following  mean  results  during 
work  on  a  somewhat  primitive  bicycle  ergometer. 


ALVEOLAR  CO2 

PERCENTAGE 

CALCULATED 

End  of 

End  of 

Mean 

RESPIRATORY 

EXCHANGE 

inspiration 

expiration 

J.  S.  H.               Rest 

I 

5-54 

570 

5.62 

Work 

4-9 

5-44 

6.05 

5-75 

J.  G.  P.               Rest 

I 

6.17 

6-39 

6.28 

Work 

3-8 

6-45 

6.98 

6.72 

Mean                   Rest 

i 

5.85 

6.045 

5.95 

Work 

4-3 

5-945 

6-545 

6.235 

In  this  series  there  was  thus  only  a  mean  rise  of  0.285  per  cent 
in  the  alveolar  CO2,  whereas  we  had  expected  to  find  a  rise  of 
about  0.6.  The  correspondence  was,  however,  in  the  right  direc- 
tion, and  we  endeavored,  mistakenly  as  afterwards  appeared,  to 
explain  the  lack  of  exact  correspondence. 

A  more  complete  series  was  carried  out  later  with  much  im- 
proved apparatus  by  Douglas  and  myself,  with  Douglas  as  sub- 
ject.12 The  accompanying  table  shows  the  data  for  volume  of  air 
breathed,  oxygen  consumed,  CO2  given  off,  composition  of  ex- 
pired air,  and  of  alveolar  air.  In  these  experiments  we  used  the 
now  well-known  bag  method  of  Douglas  for  determining  the 
respiratory  exchange.13 

It  will  be  seen  from  this  table  that  with  a  CO2  production  in- 
creased from  264  cc.  per  minute  during  rest  standing  to  1398  cc. 
per  minute  during  walking  at  4  miles  on  grass  the  alveolar  CO2 
percentage  rose  from  5.70  to  6.36,  i.e.,  by  0.66  per  cent.  The  vol- 
ume of  air  breathed  per  minute  was  increased  from  10.4  to  37.3, 

u  Douglas  and  Haldane,  Journ.  of  Physiol.,  XLV,  p.  235,  1912. 
"Douglas,  Journ.  of  Physwl.,  XLII,  Proc.  Physiol.  Soc.,  p.  xvii,   1911. 


RESPIRATION 


29 


tx  O 
COi  per   cent   in  alveolar     ON  tx 

Tj"  T^*  ^*  o    co  vO    ^"  O  OO    O 

air                                                m  to 

vO  vo  vo  vo  vO  vo  vo  vo  VO  vo 

ON  Tf 

COz  per  cent  in  expired  air     M.   M. 

10  ONOO    01    10  tx  O    01    O    ON 
01    CO  covo    iovo    iO  txOO    tx 

CO  co 

Vol.  of  each  breath  in  cc. 
at    37  0£*-   moist,    and  pre-     tx  01 
vailing     barometric     pres-      •*$•  vo 
sure. 

vo    M    coiOO    ^lO^-O    10 
010l^-ioOOOlOOO»-* 

00    w 

tXtxONOl    TtOl    01    lOCOiO 

Breaths  per  min.                      vo  ^ 

Ol    •^•rfvo    ^OO    txOOOO    ON 

Liters  of  air  breathed  per     tx 

COVO    ONOO    O    fO  01    10  co  ON 

prevailing  barometric  pres-           2 

VO  00    O    •«*•  ON  tx  rj-vo    M    O 

sure. 

COz  production  in  cc.  per      ONVO 
min.  at  o°C.  and  760  mm. 

M    01    tx  01    txOO    M  CO    O  vo 
VO  VO    co  01    10  ON  LOCO    O  CO 
iovo    txO\O    fOOl    txO    co 

M      hi      M      M      01      01 

Oz  consumption  in  cc.  per     co  01 
min.  at  o°C.  and  760  mm.      °*   ^ 

VOOO    OVOOO    O\o\o    ^    "^ 

VOtXONO     HH     LOTfO     MlO 
M      M      M      M      Ol      01      01 

}H             >-i             >-i             ^H             >-( 

$      £      S      $      $ 

C^    /'"N    C3    /^*N    rt    x^v    c^    ^"^    C^    ^*™s^ 

r^       bjOr^       fcJDr^       tU)  r^       tUO  ^H       tlJO 

g 

rt 

•ffj 

fa 

J,  JLa 

<8  £  ~ 

1  a               NCNXN 

P^^2 

;    W    W    coco^-^-^^uouo 

30  RESPIRATION 

or  by  26.9  liters.  This  corresponds  very  closely  to  the  estimate  by 
Campbell,  Douglas,  and  Hobson  of  an  increase  of  10  liters  per 
minute  in  the  breathing  for  every  .26  per  cent  of  increased  alveolar 
CO2  at  normal  barometric  pressure. 

When,  however,  the  CO2  production  was  increased  still  further, 
the  alveolar  CO2  percentage,  instead  of  continuing  to  increase, 
began  to  diminish,  and  was  only  6.10  per  cent  with  the  maximum 
CO2  production  (2386  cc.)  and  volume  of  air  breathed  (60.9 
liters).  Quite  clearly,  an  additional  factor  or  factors  besides  mere 
increase  in  the  alveolar  CO2  percentage  was  coming  into  play; 
for  with  the  higher  rates  of  CO2  production  the  lung  ventilation 
is  not  merely  increasing  in  the  same  fixed  proportion  as  before  to 
the  increased  production  of  CO2,  but  at  a  slightly  higher  rate. 
What  this  additional  factor  is  will  be  discussepl  later;  but  mean- 
while we  may  rest  content  with  the  broad  fact  that  the  increased 
ventilation  is  almost  in  proportion  to  the  increased  production  of 
CO2,  just  as  we  should  expect  from  the  other  facts  already  dis- 
cussed with  regard  to  the  regulation  of  breathing. 

It  was  shown  by  Paul  Bert14  that  the  physiological  actions  of 
CO2,  oxygen,  and  other  gases  present  in  the  air  breathed  depend 
on  their  partial  pressure.  It  is  only  when  the  barometric  pressure 
is  constant  that  their  action  depends  on  the  percentage  proportions 
in  which  they  are  present  in  the  air.  The  method  of  calculating 
the  partial  pressure  of  the  CO2  in  the  alveolar  air  may  be  illus- 
trated by  an  example.  Let  us  suppose  that  the  barometric  pressure 
is  760  mm.,  and  that  5.6  per  cent  of  CO2  is  found  in  the  alveolar 
air.  In  the  first  place  allowance  must  be  made  for  the  aqueous 
vapor  present  in  the  alveolar  air,  which  in  the  living  body  must  be 
saturated  with  aqueous  vapor  at  the  body  temperature.  The  pres- 
sure exercised  by  this  aqueous  vapor  is  47  mm.  Hence  the  remain- 
ing gas  pressure  is  760 — 47=713  mm.  Of  this  pressure  5.6  per 
cent  is  due  to  CO2  (the  results  of  the  gas  analysis  being  always  in 
terms  of  dry  air) .  Hence  the  pressure  of  CO2  is 

760 — 47 

5-6  x   =  39.9  mm.,  or  5.25  per  cent  of  an  atmosphere, 

i  oo 

since  39.9  is  5.25  per  cent  of  760. 

From  Paul  Bert's  results  it  might  be  confidently  predicted  that 
it  is  not  the  mere  percentage  but  the  pressure  of  CO2  in  the  alve- 
olar air  which  regulates  the  breathing,  and  our  experiments  left 
no  doubt  on  this  point.  On  descending  one  of  the  deepest  mines, 
and  ascending  the  highest  hill  in  Great  Britain,  we  found  that  the 

"Paul  Bert,  La  Pression  barometrique,  Paris,  1878. 


RESPIRATION  31 

pressure  of  CO2  in  the  alveolar  air  remained  about  constant,  while 
the  percentage  varied.  A  more  conclusive  experiment  was  made  in 
a  large  steel  pressure  chamber,  employed  at  the  Brompton  Hospi- 
tal, London,  for  the  treatment  of  asthma.  In  this  chamber — the 
only  one  then  existing  in  England  of  the  kind — we  compared 
our  alveolar  air  at  normal  atmospheric  pressure,  and  at  the  highest 
pressure  which  the  chamber  would  stand.  The  mean  results  were 
as  follows : 


Barometric  pressure    CO*  per  cent     CO*  pressure  in 

in  mm.  ffg. 

in  dry  alveolar        per  cent  of 

atr 

one  atmosphere 

J.  G.  P. 

I26l 

3-64 

5.83 

765 

6.41 

6.05 

J.  S.  H. 

1258 

3.42 

5.46 

765 

5.62 

S-3I 

Mean 

1260 

3.53 

5.64 

765 

6.01 

5-68 

It  is  quite  clear  from  these  results  that  it  is  the  pressure  of  CO2 
in  the  alveolar  air,  and  not  its  mere  percentage,  which  regulates 
the  breathing.  It  is  also  as  evident  from  these  experiments  as 
from  those  already  mentioned  in  which  the  oxygen  percentage 
was  varied,  that  the  oxygen  pressure  in  the  alveolar  air  may  be 
increased  very  greatly  without  at  the  time  affecting  the  regula- 
tion of  the  CO2  pressure.  The  actual  alveolar  oxygen  pressure 
was  13.0  per  cent  of  an  atmosphere  in  the  observations  at  ordinary 
pressure,  and  26.8  per  cent  in  those  at  the  high  pressure. 

Still  more  striking  results  were  obtained  by  Leonard  Hill  and 
Greenwood,15  and  by  Boycott16  in  steel  chambers  erected  later 
for  the  investigation  of  the  effects  of  high  atmospheric  pressures. 
Hill  and  Greenwood  obtained  the  following  results. 

They  considered  at  the  time  that  their  results  showed  that  the 
production  of  CO2  remained  unaltered  during  the  experiments; 
and  it  is  evident  that  had  the  volume  of  air  breathed  and  the  mass 
of  CO2  produced  remained  the  same  the  results  would  have  been 
as  they  found.  But  the  constancy  of  the  partial  pressure  of  CO2 
was  certainly  due,  not  to  the  cause  which  they  suggested,  but  to 
the  fact  that  the  breathing  was  regulated  so  as  to  keep  the  partial 
pressure  of  CO2  steady. 

"Hill  and  Greenwood,  Proc.  Roy.  Soc.,  1906,  B,  LXXVII,  p.  442,  1906. 
18  Boycott  and  Haldane,  Journ.  of  Physiol.,  XXXVII,  p.  365,  1908. 


32  RESPIRATION 


ATMOSPHERIC 
PRESSURE  IN          ALVEOLAR  CO2         ALVEOLAR  COa  PRESSURE 

IN  MM.  HG. 

PERCENTAGE 

IN  MM.  HG. 

Hill 

Greenwood 

Hill 

Greenwood 

760 

4-7 

5-3 

33-5 

37-8 

4640 

0-75 

0.9 

34-4 

4L3 

3860 

0-95 

1.0 

36.2 

38.1 

3090 

1.2 

1-3 

36.5 

39.5 

2310 

1.8 

1.8 

40.7 

40.7 

1540 

2.5 

2.7 

37-5 

40.5 

760 

5-o 

5-4 

35-6 

38.5 

The  results  of  Boycott  and  Haldane  with  Boycott  as  subject 
are  shown  graphically  in  Figure  7.  It  will  be  seen  that,  provided 
that  the  alveolar  oxygen  pressure  was  prevented  from  falling  so 
low  as  to  cause  want  of  oxygen,  the  alveolar  CO2  pressure  re- 
mained steady  with  variations  of  the  barometric  pressure  from 
300  to  2800  mm.  and  corresponding  variations  in  the  alveolar 
CO 2  percentage  from  15  to  1.5. 

The  daily  variations  of  atmospheric  pressure  at  any  one  place 
are  not  sufficiently  great  to  cause  any  considerable  variations  in 
the  alveolar  CO2  percentage,  and  there  are  other  causes,  discussed 
below,  which  cause  distinct  variations  in  the  alveolar  CO2  present. 
Even,  therefore,  if  we  take  into  consideration  the  daily  variations 
of  atmospheric  pressure,  the  resting  alveolar  CO2  pressure  is  not 
quite  constant  at  different  times  in  the  same  individual,  and  varies 
considerably  in  different  individuals. 

The  differences  in  the  alveolar  CO2  pressure  in  different  indi- 
viduals, and  in  different  sexes  and  at  different  ages,  were  investi- 
gated by  Miss  Fitz  Gerald  and  myself.  We  obtained  the  following 
results  from  a  number  of  different  persons,17  living  at  Oxford. 


ALVEOLAR  COa  PRESSURES  IN  MM.  OF  MERCURY 

Mean 

Maximum 

Minimum 

Men 

39-2 

44-5 

32.6 

Women 

36.3 

41.0 

30.4 

Boys 

37-2 

42.1 

30.6 

Girls 

35-2 

40.1 

31.2 

17  Haldane  and  FitzGerald,  Journ,  of  Physiol.,  XXXII,  p.  491,  1905. 


RESPIRATION 


33 


The  investigations  of  Priestley  and  myself  brought  out  the 
remarkable  fact  that  the  composition  of  the  alveolar  air  is  the 
same  no  matter  how  deep  the  breath  may  be  from  the  last  portion 
of  which  the  sample  is  taken.  According  to  descriptions  commonly 


3000       2600 


200     0 


2200       1800        1400        1000 
air  pressure  mm  Hg 

Figure  7. 

Effects  of  variation  in  barometric  pressure  on  alveolar  gas  pres- 
sures and  percentage  of  CO2  in  A.  E.  B.  The  dotted  lines  show  results 
•when  oxygen  was  added  to  the  air. 

current  of  the  anatomical  relations  of  bronchioles  to  alveoli  one 
would  have  expected  that  the  deeper  parts  of  a  breath,  coming 
from  alveoli  far  from  the  bronchioles,  would  contain  more  CO2, 
since  these  alveoli  must  get  less  fresh  air  than  the  alveoli  near  a 
bronchiole.  It  was  somewhat  of  a  puzzle  that  this  was  not  the  case. 
I  was  unaware  of  the  anatomical  investigations  which  had  been 
carried  out  ten  years  earlier  by  a  distinguished  American  investi- 
gator, W.  S.  Miller,  who  by  using  the  laborious  "reconstruction" 
method  had  discovered  the  true  anatomical  arrangement.18  Figure 
8,  modified  from  a  colored  plate  in  Miller's  latest  paper,  shows 

18  Miller,  Journ.  of  Morphol.,  VIII,  p.  165,  1893,  and  XXIV,  p.  459,  1913. 


34 


RESPIRATION 


diagrammatically  this  arrangement.  The  finest  ordinary  bronchi- 
oles divide  up  to  form  "respiratory  bronchioles"  with  alveoli  in 


Figure  8. 

Diagram  showing  arrangement  of  three  lung  lobules,  with  their 
bronchiole,  respiratory  bronchioles,  alveolar  ducts,  atria,  and  air- 
sacs.  (After  colored  plate  by  Miller,  Journ.  of  Morphol.  24,  p.  459, 
1913.) 

their  walls,  and  the  respiratory  bronchioles  branch  into  "alveolar 
ducts"  lined  with  ordinary  alveoli,  and  each  opening  into  from 


RESPIRATION  35 

two  to  five  distributing  chambers  which  he  named  "atria,"  and 
which  are  also  lined  with  alveoli.  From  each  atrium  a  number  of 
openings  lead  onwards  into  what  he  calls  "air- sacs,"  which  are 
main  cavities  of  which  the  walls  are  also  constituted  of  alveoli  or 
air  cells.  By  far  the  greater  part  of  the  alveoli  belong  to  the  air- 
sac  system,  but  a  certain  number  belong  to  the  respiratory  bron- 
chioles, alveolar  ducts  and  atria;  and  the  latter  act  partly  as  air 
passages  to  the  air  sacs,  and  partly  perform  the  same  respiratory 
functions  as  the  air  sacs  themselves. 

With  this  anatomical  arrangement  the  whole  of  an  air-sac  sys- 
tem is  about  equally  well  ventilated  with  fresh  air,  the  only  alveoli 
which  receive  an  undue  supply  of  fresh  air  being  those  of  the 
respiratory  bronchioles,  alveolar  ducts  and  atria.  We  can  thus 
understand  why  it  is  that  the  deeper  parts  of  a  very  deep  breath 
have  exactly  the  same  composition  as  the  middle  parts.  Evidently 
however  what  Priestley  and  I  called  "alveolar  air"  is  air-sac  air. 

The  fact  that  the  atria,  etc.,  have  partly  a  respiratory  function, 
and  partly  act  as  air  passages  to  the  air-sac  system,  enables  us 
also  to  clear  up  some  otherwise  unintelligible  facts  with  regard 
to  the  "dead  space"  in  breathing.  The  dead  space  was  first  esti- 
mated roughly  by  Loewy  from  the  volume  of  a  cast  of  the 
respiratory  passages,  taken  in  a  human  lung  after  death.  As  this 
method  seemed  uncertain,  Priestley  and  I  made  determinations  by 
comparing  the  composition  of  a  whole  breath  of  expired  air  with 
the  composition  of  what  we  took  to  be  the  whole  alveolar  air.  We 
calculated  the  expired  air  as  a  mixture  of  this  alveolar  air  with 
fresh  air  occupying  the  dead  space.  In  this  way  we  found  that 
during  rest  the  volume  of  the  "effective  dead  space"  is  about 
30  per  cent  of  the  volume  of  the  average  tidal  air.  For  greater 
certainty  Douglas  and  I  collected  the  whole  of  the  expired  air 
over  a  certain  period,  and  made  the  same  calculation  from  the 
average  volume  and  composition  of  each  breath,  compared  with 
the  composition  of  the  alveolar  air.19  We  then  found  that  the 
"effective  dead  space"  is  far  greater  during  the  hyperpnoea  of 
hard  muscular  work  than  during  rest.  As  we  were  then  still  un- 
aware of  Miller's  work  we  interpreted  our  observations  as  indicat- 
ing that  the  bronchi  or  other  respiratory  passages  become  wider 
during  hyperpnoea,  so  as  to  enable  air  to  enter  the  lungs  more 
easily.  Any  one  who  examines  a  section  of  lung  must  be  struck  at 
once  by  the  fact  that  the  mucous  membrane  of  the  bronchi  is 
usually  in  folds,  indicating  that  if  the  muscular  coat  relaxed  the 

19  Douglas  and  Haldane,  Journ.  of  Physwl.,  XLV,  p.  235,  1912. 


36  RESPIRATION 

folds  would  open  out  and  the  lumen  of  the  bronchi  would  greatly 
increase.  We  thought  it  probable  that  such  a  relaxation  occurs 
during  hyperpnoea,  and  that  this  explains  the  increase  of  the  dead 
space. 

Using  a  method  which  Siebeck  first  introduced,  Krogh  and 
Lindhard20  then  redetermined  the  dead  space,  and  concluded  that 
it  does  not  appreciably  increase  during  hyperpnoea.  Their  method 
was  to  take  in  a  small  measured  breath  of  a  hydrogen  mixture: 
they  then  made  a  deep  expiration,  which  was  measured,  and 
from  the  deeper  part  of  which  a  sample  of  the  alveolar  air  was 
taken.  From  the  percentage  of  hydrogen  in  the  alveolar  air,  as 
compared  with  the  higher  percentage  in  the  whole  expired  air,  the 
volume  of  the  dead  space  could  be  calculated  on  the  assumption 
that  it  was  filled  with  the  original  hydrogen  mixture. 

The  question  was  then  independently  reinvestigated  about  the 
same  time  by  Yandell  Henderson,  Chillingworth,  and  Whitney  at 
Yale,  and  myself  at  Oxford.  We  reached  the  same  conclusion — 
namely  that  the  apparent  effective  dead  space  is  enormously  in- 
creased during  hyperpnoea,  as  Douglas  and  I  had  found,  but  that 
the  increase  is  due  simply  to  mechanical  causes,  and  occurs 
whether  or  not  the  respiratory  center  is  excited  by  excess  of  CO2 
or  other  causes.  Our  papers  appeared  together  in  the  American 
Journal  of  Physiology.2^  In  their  determinations  Krogh  and 
Lindhard  had  inspired  the  same  volume  of  the  hydrogen  mixture 
whether  there  was  air  hunger  at  the  time  or  not,  and  consequently 
they  got  the  same  dead  space;  whereas  our  experiments  were 
made  with  the  very  deep  breathing  which  is  naturally  associated 
with  air  hunger,  and  consequently  the  dead  space  was  increased. 

Miller's  investigations  enable  us  to  explain  the  great  increase 
of  the  "effective  dead  space"  with  deep  inspirations.  Considering 
the  relative  thickness  and  stoutness  of  the  bronchial  walls  it  seems 
very  improbable  that  the  bronchi,  surrounded  as  they  are  by  very 
yielding  lung  tissue,  could  passively  dilate  appreciably  owing  to 
a  deeper  inspiration,  and  this  consideration  led  Douglas  and 
me  to  believe  that  they  must  dilate  owing  to  a  relaxation  of 
their  muscular  walls — a  theory  negatived  by  the  later  experi- 
ments. What  dilate  during  deep  breathing  are  evidently  not  the 
bronchi  but  Miller's  "alveolar  ductules"  and  "atria,"  which  serve 
as  air  passages  to  the  "air-sacs,"  and'  which  must  expand  along 

20  Krogh  and  Lindhard,  Journ.  of  Physwl.,  XLVIII,  p.  30,  1913. 

21  Yandell  Henderson,  Chillingworth,  and  Whitney;  also  Haldane,  Amer.  Journ. 
of  Physiol.,  XXXVIII,  pp.  i  and  20,  1915. 


RESPIRATION  37 

with  the  general  expansion  of  the  lungs.  In  addition,  they  are  more 
completely  washed  out  by  fresh  air  during  inspiration.  It  also  fol- 
lows that  the  "effective  or  virtual  dead  space"  is  neither  a  definite 
anatomical  space  nor  a  fixed  dead  space  in  any  sense,  but  a  value 
dependent  on  several  variable  factors.  These  factors  include  the 
rates  at  which  CO2  passes  outwards  and  oxygen  passes  inwards 
between  the  air  and  blood  at  different  points  in  the  alveolar  sys- 
tem. For  this  reason  the  "effective  dead  space"  is  different  for 
oxygen  and  CO2.  The  over-ventilation  of  the  atria,  etc.,  removes 
from  the  blood  circulating  round  them  an  extra  proportion  of 
carbon  dioxide,  but  cannot,  for  a  reason  which  will  be  discussed 
later,  give  to  the  blood  any  appreciable  extra  amount  of  oxygen. 
During  inspiration  this  extra  proportion  of  CO2  passes  on  to  the 
saccular  alveoli,  but  not  during  expiration.  The  "respiratory 
quotient,"  or  ratio  between  the  volume  of  carbon  dioxide  given 
off  and  of  oxygen  absorbed,  is  thus  abnormally  high  in  the  air 
expired  from  the  atria,  etc.,  and  as  a  consequence  abnormally 
low  in  the  air  sacs,  so  that  the  "effective  dead  space,"  as  calculated 
from  deficiency  of  oxygen  in  the  expired  air,  compared  with  that 
in  the  "alveolar  air,"  is  greater  than  when  the  dead  space  is  calcu- 
lated from  the  relative  CO2  percentages.  The  respiratory  quotient 
for  the  "alveolar  air"  is  also  below  the  correct  value  as  calculated 
from  the  composition  of  the  mixed  expired  air. 

The  following  table,  giving  results  on  myself,  shows  the  varia- 
tions in  the  "effective  dead  space"  with  varying  depth  of  breathing 
as  calculated  both  from  CO2  and  from  oxygen,  and  also  the  differ- 
ences between  the  respiratory  quotient  as  calculated  from  the 
expired  air  and  from  the  alveolar  air.  Using  a  slightly  different 
method,  Henderson,  Chillingworth,  and  Whitney  got  similar  re- 
sults. 

It  will  be  seen  from  this  table  how  enormously  the  apparent 
dead  space  varies  with  the  depth  of  breathing  and  how  much 
greater  the  dead  space  calculated  from  the  oxygen  is  than  that 
calculated  from  the  CO2.  A  further  point  which  comes  out  is  that 
with  deep  breathing  the  difference  between  the  alveolar  CO2 
percentages  at  the  beginning  and  end  of  expiration  is  far  less  than 
the  difference  between  the  oxygen  percentages.  This  is  mainly 
because  the  extra  CO2  washed  out  of  the  alveolar  ductules  and 
atria  passes  on  into  the  saccular  alveoli  during  inspiration.  A 
further  point  is  that  the  true  respiratory  quotient  is  about  a  sixth 
higher  than  the  alveolar  respiratory  quotient.  The  fact  that  the 
alveolar  respiratory  quotient  is  a  good  deal  lower  than  the  true 


38 


RESPIRATION 


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RESPIRATION  .  39 

quotient  had  been  noticed  by  us  before  this  in  the  work  of  the 
Pike's  Peak  Expedition  (to  be  referred  to  later),  but  had  not  been 
explained.  It  is  quite  evident  from  the  table  that  the  composition 
of  the  deep  alveolar  air  cannot  be  even  approximately  calculated 
from  that  of  the  expired  air  by  assuming  the  existence  of  a  con- 
stant dead  space.  The  latter  assumption  has  caused  great  confusion 
in  recent  years,  particularly  in  the  work  of  the  Copenhagen  School. 
It  was  shown  by  Yandell  Henderson  and  his  coadjutors  that 
when  air  passes  along  an  air  passage  the  axial  stream  is  much 
faster  than  the  peripheral  stream,  and  that  as  a  consequence  of 
this  the  air  in  the  dead  space  is  not  pushed  out  bodily  in  front  of 
the  alveolar  air  during  expiration.  Some  of  the  tracheal  and 
bronchial  air  is  at  first  left  behind,  and  before  pure  alveolar  air 
issues  at  the  nose  or  mouth  the  air  passages  have  to  be  washed  out 
by  three  or  four  times  their  volume  of  alveolar  air.  This  is  illus- 


;r:'^ 


Figure  9. 

(a)  Shows  a  "spike"  of  smoke  moving  through  a  glass  tube,  (b) 
Shows  the  condition  when  the  current  is  suddenly  stopped  and  mixing 
instantaneously  occurs,  (c)  Shows  clear  air  drawn  in. 


Figure  10. 

Shows  how  a  column  of  smoke  crosses  a  bulb  with  little  mixing 
or  sweeping  out  of  the  air  within  it. 

trated  by  Figures  9  and  10,  taken  from  their  paper,  and  drawn 
from  experiments  made  with  smoke.  Both  they  and  I  found  also 
that  a  pause  before  expiration  diminishes  the  volume  of  the  ap- 
parent dead  space.  This  is  easily  understood,  as  the  air  in  the 
atria,  etc.,  will  during  the  pause  come  nearer  in  composition  to 
that  of  the  saccular  alveoli.  With  care  in  avoiding  a  pause  I  found 


40  RESPIRATION 

that  during  rest  with  normal  breathing  it  was  necessary  to  expire 
about  800  cc.  of  air  before  a  reliable  alveolar  sample  could  be 
obtained  at  the  end  of  inspiration.  If  the  breathing  was  deep  and 
slow  much  more  air  had  to  be  expired.  At  the  end  of  a  normal 
expiration,  however,  the  air  issuing  from  the  mouth  is  practically 
alveolar  in  composition. 

The  conclusion  reached  by  Priestley,  Douglas,  and  myself  that 
increased  production  of  CO2,  and  consequent  rise  in  the  alveolar 
CO2  percentage,  determines  increased  breathing  during  muscular 
work  was  afterwards  questioned  by  Krogh  and  Lindhard,22  on 
the  ground  that  our  determinations  of  the  alveolar  CO2  percentage 
were  fallacious,  and  that  the  real  alveolar  CO2  percentage  during 
muscular  work  is  not  only  lower  than  we  found,  but  also  con- 
siderably lower  than  during  rest.  Their  argument  is  mainly 
based  on  the  assumptions,  which  have  already  been  shown  to  be 
wrong,  that  the  "effective  dead  space"  is  not  largely  increased 
during  deep  breathing,  and  that  reliable  samples  of  alveolar  air 
can  be  obtained  at  the  end  of  a  deep  inspiration,  without  more 
than  a  very  shallow  expiration  to  clear  the  extra  dead  space.  This 
part  of  their  argument  falls  to  the  ground.  They  point  out,  how- 
ever, what  is  a  real  source  of  slight  error — namely  that  a  delay  of 
fully  half  a  second  occurs  during  the  taking  of  an  alveolar  sample, 
and  that  during  this  interval  the  alveolar  CO2  percentage  must 
rise  appreciably.  It  was  shown  above  that  the  difference  in  CO2 
percentage  between  samples  of  alveolar  air  taken  at  the  beginning 
and  end  of  expiration  during  work  corresponding  to  an  increase 
of  4.3  times  in  the  CO2  production  was  about  0.6  per  cent.  As  an 
expiration  took  nearly  2  seconds,  there  would  be  a  rise  of  0.15  per 
cent  in  half  a  second,  corresponding  to  the  delay  in  taking  the 
alveolar  sample.  During  rest,  according  to  a  similar  calculation, 
there  would  be  a  rise  of  0.05  per  cent.  The  net  error  in  comparing 
rest  with  work  would  thus  be  only  about  o.  I  per  cent,  a  difference 
too  small  to  affect  the  conclusions  materially.  Owing  to  their 
defective  methods  of  estimating  and  directly  determining  the 
alveolar  CO2  percentage  at  the  beginning  of  expiration  Krogh 
and  Lindhard  enormously  overestimated  the  error  due  to  a  delay 
of  half  a  second  in  obtaining  a  sample.  The  fact  remains,  however, 
that  when  the  work  was  pushed  in  the  case  of  Douglas,  and  even 
without  pushing  the  work  in  my  own  case,  the  rise  in  alveolar  CO2 
percentage  was  less  than  corresponded  to  the  increase  in  breathing. 
This  significant  fact  will  be  discussed  later. 

22  Krogh  and  Lindhard,  Journ.  of  Physiol.,  XLVIII,  p.  30,  1913. 


RESPIRATION  41 

It  will  be  shown  in  Chapter  IX  that  during  rest  under  normal 
conditions  the  gas  pressures  in  the  alveolar  air  and  blood  passing 
through  the  alveoli  come  into  exact  equilibrium.  Now  it  has  just 
been  shown  that  in  a  very  appreciable  part  of  the  lung  alveoli 
(those  in  the  respiratory  bronchioles,  alveolar  ducts,  and  atria) 
the  CO2  pressure  is  lower,  and  the  oxygen  pressure  higher,  than 
in  the  air-sac  alveoli.  We  might  therefore  be  led  to  infer  that  in 
the  mixed  arterial  blood  the  CO2  pressure  will  be  lower,  and  the 
oxygen  pressure  higher,  than  in  the  blood  from  the  air-sac  alveoli, 
and  that  in  consequence  of  this  the  mixed  arterial  blood  will  have 
-a  lower  CO2  pressure  than  that  of  the  deep  alveolar  air.  Further 
consideration  shows,  however,  that  this  will  not  be  the  case.  The 
walls  of  the  alveoli  of  respiratory  bronchioles,  etc.,  are  in  contact 
on  the  one  side  with  the  air  of  air-passages,  but  on  the  other  with 
air  in  the  air-sac  alveoli.  Hence  the  extra  proportion  of  CO., 
extracted  from  the  blood  in  the  air-passage  alveoli  is  practically 
taken  from  the  air-sac  alveoli,  and  this  is  why  the  apparent  respira- 
tory quotient  of  the  air-sac  alveoli  is  lower  than  the  true  respira- 
tory quotient.  We  should  be  counting  the  lowering  twice  if  we  as- 
sumed that  in  consequence  of  the  extra  discharge  of  CO2  in  the  re- 
spiratory bronchioles,  etc.,  the  CO2  pressure  of  the  arterial  blood  is 
lower  than  corresponds  to  that  of  the  air-sac  alveoli.  The  same 
argument  applies  also  as  regards  the  oxygen  pressure  of  the  air- 
sac  air,  although  under  normal  conditions  hardly  any  extra  oxy- 
gen can  pass  into  a  given  volume  of  blood  in  its  passage  through 
the  alveoli  of  respiratory  bronchioles,  etc.  Hence  the  gas  pressures 
of  the  air-sac  alveoli  represent  truly  the  mean  gas  pressures  to 
which  the  arterial  blood  is  saturated  in  the  various  alveoli.  This 
is  why  the  gas  pressures  of  the  deep  alveolar  air  as  determined  by 
the  method  which  Priestley  and  I  introduced  are  of  so  much 
importance. 

Krogh  and  Lindhard23  still  maintain  that  the  mean  gas  pres- 
sures to  which  the  blood  is  equilibrated  in  passing  through  the 
lungs  is  given,  not  by  the  composition  of  the  deep  alveolar  air, 
but  by  that  of  the  alveolar  air  as  calculated  from  a  fixed,  or  almost 
fixed,  dead  space.  This  involves  the  conclusion  that  during  deep 
breathing,  including  the  deep  breathing  of  muscular  exertion,  the 
arterial  CO2  pressure  is  far  lower  than  is  shown  by  the  direct 
method  of  Priestley  and  myself.  As,  however,  there  is  no  cor- 
responding apnoea,  the  whole  theory  of  regulation  of  breathing  in 
accordance  with  the  CO2  pressure  of  the  arterial  blood  must  be 

23  Krogh  and  Lindhard,  Journ.  of  Pkysiol.,  LI,  p.  59,  1917. 


42  RESPIRATION 

abandoned  if  Krogh  and  Lindhard  are  correct.  Their  reasoning 
is  quite  logical,  but  their  premises  are  unsound.  They  have  failed 
to  take  into  consideration  trje  anatomical  relations  of  the  air- 
passage  alveoli  to  the  air-sac  alveoli. 

The  fact  that  the  mixed  air  from  all  the  air  sacs  of  the  lungs  is 
the  same  in  composition  however  much  of  this  air  is  expelled  in 
taking  a  sample  led  us  to  assume  almost  unconsciously  that  the 
composition  of  the  air  in  practically  all  the  air  sacs  is  the  same. 
Nevertheless  all  that  the  experiments  prove  is  that  the  average 
composition  of  the  air  expelled  from  the  air  sacs  is  the  same,  while 
in  individual  air  sacs  the  composition  may  vary  widely. 

It  is  evident  that  in  any  particular  air-sac  system  the  mean 
composition  of  the  contained  air  will  depend  on  the  ratio  between 
the  supply  of  fresh  air  and  the  flow  of  blood.  If  the  supply  of 
fresh  air  is  unusually  small  in  relation  to  the  supply  of  venous 
blood  there  will  be  a  lower  percentage  of  oxygen  and  higher 
percentage  of  carbon  dioxide  in  the  air  of  the  air  sac,  and  vice 
versa.  It  seems  probable  that  by  some  means  at  present  unknown 
to  us  a  fair  adjustment  is  maintained  normally  between  air  supply 
and  blood  supply.  For  instance,  the  muscular  walls  of  bronchioles 
may  be  concerned  in  adjusting  the  air  supply,  or  the  arterioles 
or  capillaries  may  contract  or  dilate  so  as  to  adjust  the  blood 
supply.  In  any  case  what  seems  to  matter  is  the  degree  of  arteri- 
alization,  not  of  the  blood  from  individual  air  sacs,  but  of  the 
mixed  arterial  blood;  and  if  the  composition  of  the  mixed  air-sac 
air  served  as  a  reliable  index  of  the  arterialization  of  the  mixed 
arterial  blood  we  might  dismiss  as  a  matter  of  only  academic 
interest  the  question  whether  the  air  in  individual  air  sacs  varies 
in  composition. 

It  will  be  shown  below  that  there  can  be  little  doubt  that  under 
normal  conditions  the  air  in  different  air  sacs  varies  appreciably 
in  composition,  and  that  under  abnormal  conditions  the  variation 
may  be  considerable.  It  will  also  be  shown  that  the  latter  fact 
is  one  of  great  importance  in  pathology  and  therapeutics. 

Meanwhile  it  is  clear  from  the  experiments  described  in  the 
present  chapter  that  under  normal  conditions,  excluding  heavy 
work,  the  breathing  in  man  is  on  an  average  regulated  by  the  al- 
veolar CO2  pressure ;  and  a  very  slight  increase  or  diminution  in 
the  alveolar  CO2  pressure  suffices  to  cause  a  very  great  increase  or 
diminution  in  the  breathing.  This  conclusion  has  thrown  a  flood 
of  clear  light  on  the  physiology  of  breathing. 


CHAPTER  III 
The  Nervous  Control  of  Breathing. 

IT  is  now  necessary  to  discuss  more  closely  the  influence  of  nervous 
control  on  breathing.  The  rhythmic  activity  of  the  respiratory 
center  is  for  short  periods  of  time  very  completely  under  volun- 
tary control — a  fact  evidently  connected  with  the  very  delicate 
use  of  the  lungs  in  phonation,  as  well  as  in  other  voluntary  acts  not 
directly  connected  with  "chemical"  respiratory  functions.  Excita- 
tion of  various  afferent  nerves  may  also  excite  or  inhibit  inspira- 
tion or  expiration.  Most  of  the  effects  thus  produced  appear  to  be 
protective  in  various  ways,  or  preparatory  to  some  particular 
effort,  and  they  only  disturb  the  main  regulation  of  breathing 
occasionally,  just  as  voluntary  interference  does.  In  view  of  the 
facts  with  regard  to  the  control  of  breathing  by  chemical  stimuli, 
we  might  thus  be  led  to  the  conclusion  that  the  respiratory  center, 
when  not  interfered  with  by  voluntary  or  other  occasional  nervous 
disturbances,  acts  simply  by  producing  rhythmic  inspiratory  and 
expiratory  discharges,  determined  in  extent  and  frequency  by 
nothing  but  chemical  stimuli  dependent  on  the  blood  supply. 

This  simple  conception  is  entirely  inadequate,  in  view,  more 
particularly,  of  the  facts  discovered  originally  by  Hering  and 
Breuer,  and  already  referred  to.  These  facts,  apart  from  the 
results  of  section  of  the  vagi,  can  be  observed  very  fully  in  man, 
without  the  complications  introduced  by  anaesthetics,  and  were 
so  studied  in  1916  by  Mavrogordato  and  myself.1  We  employed 
a  very  simple  arrangement  which  enabled  us  to  breathe  through 
a  wide-bored  tap,  and  observe  by  a  water  manometer  the  pres- 
sure between  the  mouth  and  the  tap  when  the  latter  was  closed, 
the  nostrils  being  closed  by  a  clip.  If  the  tap  was  closed  at 
the  end  of  natural  or  forced  inspiration  or  expiration,  or  in 
any  other  phase  of  respiration,  the  phenomena  could  be  studied. 
By  connecting  the  far  end  of  the  tap  with  a  reservoir  containing 
pure  air  or  air  containing  any  required  percentage  of  CO2,  we 
could  observe  the  influence  of  hyperpnoea  due  to  CO2,  and  by 
suitable  volume  recorders  connected  with  the  far  ends  of  the 
reservoir  and  gauge  the  breathing  and  pressure  could  be  recorded. 

If  expiration  is  interrupted  by  turning  the  tap,  and  all  voluntary 

1  Journ.  of  Physiol.,  L;  Proc.  Physiolog.  Soc.,  p.  xli,  1916. 


44  RESPIRATION 

effort  is  suspended,  the  previous  rhythm  of  the  respiratory  center 
is  interrupted  by  a  prolonged  expiratory  phase,  as  indicated  by 
the  gauge.  The  expiratory  pressure  is  at  first  slight  and  constant, 
but  afterwards  rises  gradually  and  at  an  increasing  rate,  until, 
if  expiration  is  still  prevented,  there  is  at  length  an  inspiratory 
effort,  as  shown  in  Figure  n.  Similarly,  if  the  breathing  is  ob- 


RESPIRATION 


/NTPAPULMONARY  PRESSURE 


RESPIRATION 


I NTRAPULMONARY  PRESSURE 


Figure  i i . 

Effects  of  interrupting  natural  breathing.  A.  Respiration  inter- 
rupted during  inspiration — near  end.  B.  Respiration  interrupted 
during  expiration — near  end.  Respirations — inspiration  up,  expira- 
tion down.  Intrapulmonary  pressure — positive  pressure  down,  neg- 
ative pressure  up. 

structed  during  expiration  there  is  a  prolonged  and  increasing 
inspiratory  effort  (Figure  n).  The  initial  inspiratory  pressure 
is  somewhat  greater  than  the  initial  expiratory  pressure,  and  this 
is  in  accordance  with  the  opinion  generally  held  that  while  ordi- 
nary quiet  inspiration  is  always  an  active  process  the  correspond- 
ing expiration  is  mainly  passive. 

With  interruption  at  the  end  of  an  extra  deep  inflation  or  de- 
flation of  the  lungs  the  phenomena  are  still  more  marked.  If 
apnoea  has  previously  been  caused  by  forced  breathing,  the  initial 
expiratory  or  inspiratory  pressures  are  still  produced  as  before, 
but  a  long  interval  elapses  before  they  begin  to  increase,  and  the 
duration  of  the  expiratory  or  inspiratory  phase  is  much  prolonged. 


RESPIRATION  45 

If,  on  the  other  hand,  the  inflation  or  deflation  was  made  during 
the  hyperpnoea  caused  by  breathing  air  containing  an  excess  of 
CO2  the  expiratory  or  inspiratory  pressures  mount  up  at  onre. 
The  mounting  up  of  the  initial  pressure  is  thus  dependent  on  the 
accumulating  chemical  stimulus  to  the  respiratory  center.  If  the 
breathing  is  interrupted,  not  just  after,  but  before  the  completion 
of  inspiration  or  expiration,  the  inspiratory  phase  is  continued  if 
inspiration  has  been  interrupted,  and  the  expiratory  if  expiration 
has  been  interrupted,  as  shown  in  Figure  II. 

If,  instead  of  interrupting  the  breathing  by  means  of  a  tap  or 
other  obstacle  which  cannot  be  overcome,  the  only  interruption 
is  by  a  limited  adverse  pressure  capable  of  being  overcome  by 
the  breathing,  the  apparent  "apnoea"  is  terminated  by  an  expira- 
tion if  the  pressure  is  positive,  or  an  inspiration  if  the  pressure  is 
negative.  This  simply  means  that  with  a  positive  pressure  the 
expiration  occurs  at  the  moment  when  the  expiratory  effort  has 
increased  sufficiently  to  overcome  the  adverse  positive  pressure, 
and  similarly  with  a  negative  pressure.  This  is  illustrated  by 
Figures  12  and  13,  which  reproduce  stethographic  tracings  ob- 
tained in  man.2  The  subject  at  first  breathed  quietly  through  the 
limb  of  a  wide-bore  three-way  tap  open  to  the  air.  At  the  end  of 
an  inspiration  the  tap  was  suddenly  turned  so  that  the  mouth  of 
the  subject  was  connected  with  the  air  of  a  bag  under  a  pressure 
of  about  3  inches  of  water.  The  consequence  of  this  was  that  the 


Figure  12. 


Figure  13. 

Effects  of  prolonged  distention  of  the  lungs.  To  be  read  from  left  to  right.  Time 
marker  =  seconds.  Distention  continued  between  the  two  crosses.  In  Fig.  12  pure 
air  was  used  for  distention;  in  Fig.  13  air  containing  7.3  per  cent  of  COa  and 
8.2  per  cent  of  oxygen. 

lungs  were  suddenly  distended  with  a  large  volume  of  air.   It 
will  be  seen  that  after  about  half  a  minute  the  apparent  pause  in 

'Christiansen  and  Haldane,  Journ.  of  Physiol.,  XLVIII,  p.  272,  1914. 


46  RESPIRATION 

the  breathing  was  interrupted  by  an  expiration,  repeated  after- 
wards at  gradually  diminishing  intervals.  The  diminution  in 
these  intervals  was  evidently  due  to  the  fact  that  CO2  was  ac- 
cumulating in  the  lungs;  and  this  interpretation  is  confirmed  by 
Figure  13. 

Figure  14  shows  a  corresponding  effect  with  a  negative  pressure 
applied,  so  as  partially  to  deflate  the  lungs.  In  this  case  the  ap- 
parent pause  was  much  shorter,  as  CO2  began  to  accumulate  very 
rapidly,  owing  to  the  facts  that  not  only  had  no  fresh  air  been 
introduced,  but  the  volume  of  air  in  the  lungs  was  diminished. 


Figure  14. 

Effects  of  partial  deflation.  Crosses  show  beginning  and  end  of 
deflation.  To  read  from  left  to  right.  Time-marker  =  i  second. 

The  supposed  apnoeic  pause  produced  by  distention  or  inflation 
of  the  lungs  is  simply  a  prolonged  inspiratory  or  expiratory  effort. 
This  effect  is  produced  regardless  of  the  chemical  stimulus  to  the 
center.  Thus  Lorrain  Smith  and  I  showed  that  it  is  even  produced 
when  the  lungs  are  distended  with  air  containing  20  per  cent  of 
CO2,  though  the  prolongation  is  much  curtailed  in  such  a  case.3 

It  is  thus  clear  that  the  continuance  of  an  inspiratory  or  ex- 
piratory discharge  of  the  respiratory  center  depends  on  the  extent 
to  which  actual  inspiration  or  expiration  accompanies  the  dis- 
charge. If  the  movements  of  inspiration  or  expiration  are  not 
accomplished  the  ordinary  respiratory  rhythm  is  replaced  by  a 
prolonged  and  increasingly  powerful  inspiratory  or  expiratory 
discharge,  tending  to  overcome  the  obstruction.  The  respiratory 
center  does  not  act  independently  of  the  lung  movements,  but 
inspiratory  or  expiratory  discharge  of  the  center  goes  hand  in' 
hand  with  actual  inspiration  or  expiration,  as  if  the  center  were 
one  piece  with  the  lungs.  The  term  "vagus  apnoea"  is  evidently 
an  entire  misnomer,  as  prolonged  inspiratory  or  expiratory  effort 
cannot  be  called  apnoea.  The  tracings  which  apparently  demon- 
strate the  existence  of  apnoea  are  only  one-sided,  and  therefore 
misleading,  records. 

Hering  and  Breuer  found,  as  already  mentioned  in  Chapter  I, 
that  after  section  of  both  vagi  the  association  of  discharge  of  the 

1  Haldane  and  Lorrain  Smith,  Journ.  of  Pathology,  I,  p.  168,   1892. 


RESPIRATION  47 

center  with  the  respiratory  movements  is  annulled,  so  that  infla- 
tion or  deflation  of  the  lungs  has  no  immediate  influence  on  the 
respiratory  rhythm.  Hence  the  afferent  impulses  through  which 
the  discharges  of  the  center  are  coordinated  with  the  movements 
of  the  lungs  are  conveyed  by  the  vagi.  After  section,  or  better  (so 
as  to  avoid  excitatory  effects  produced  by  actual  section),  freezing 
of  the  vagi,  the  breathing,  as  has  been  known  since  early  last 
century,  becomes  deeper  and  less  frequent,  the  inspirations  in 
particular  taking  on  a  dragging  character  which,  until  the  work 
of  Schafer,  referred  to  below,  was  entirely  attributed  to  the  ab- 
sence of  the  normal  inhibitory  effect  conveyed  through  the  vagi 
on  distention  of  the  lungs  to  a  certain  point.  Nevertheless  the 
respirations  continue  to  be  rhythmic,  and  to  respond  in  their  depth 
to  the  stimulus  dependent  on  varying  percentages  of  CO2  in  the 
alveolar  air.  It  was  shown  by  Scott4  however,  that  the  control  of 
the  alveolar  CO2  percentage  when  excess  of  CO2  is  present  in  the 
air  breathed  becomes  much  less  perfect,  as  the  frequency  of  the 
breathing  cannot  increase. 

The  analogy  between  the  Hering-Breuer  stimuli  transmitted 
through  the  vagi  and  what  Sherrington  has  named  the  "proprio- 
ceptive"  stimuli  participating  in  reflex  or  voluntary  movements 
of  the  limbs  is  evident;  though  the  rhythmic  discharges  of  the 
respiratory  center  are  dependent  on  stimuli,  not  from  the  surface 
of  the  body,  but  from  the  blood  acting  on  the  center. 

When,  in  addition  to  section  of  the  vagi,  the  respiratory  center 
is  also  severed  from  its  connections  above  the  medulla  oblongata, 
the  rhythmic  discharges  of  the  center  become  still  less  frequent, 
and  may  be  inadequate  to  prevent  death  from  asphyxia.  The 
influence  on  the  center  of  afferent  stimuli  from  the  respiratory 
muscles  has  not  yet  been  demonstrated  directly;  but  the  fact, 
observed  by  Boothby  and  Shamoff,5  that  an  animal  in  which  the 
pulmonary  branches  of  the  vagi  have  been  severed  without  injury 
to  the  recurrent  laryngeal  nerve  recovers  after  a  sufficient  time 
a  normal  control  over  respiration  seems  to  point  to  the  existence 
of  such  stimuli.  The  same  conclusion  has  been  still  more  clearly 
reached  in  a  quite  recent  paper  by  Schafer,6  who  shows  that  the 
slowed  breathing  after  section  of  the  vagi  is  largely  due  to  ob- 
struction caused  by  laryngeal  paralysis. 

We  must  now  endeavor  to  correlate  the  facts  relating  to  the 

4  Scott,  Journ.  of  Physwl.,  XXXVII,  p.  301,  1908. 

5  Boothby  and  Shamoff,  Amer.  Journ.  of  Physwl. ,  XXXVII,  p.  418,   1913. 
9  Schafer,  Quart,  Journ.  of  Exper.  Physiol.,  XII,  p.  231,  1919. 


48  RESPIRATION 

Hering-Breuer  phenomena  with  those  relating  to  the  governing 
of  the  lung  ventilation  by  the  charge  of  CO2  in  the  alveolar  air 
and  arterial  blood.  It  seems  very  clear  that  the  immediate  cause  of 
the  arrest  of  inspiration  during  ordinary  breathing  is  the  disten- 
tion  of  the  lungs  to  a  certain  point,  and  a  consequent  inhibitory 
stimulus  transmitted  up  the  vagi.  The  experiments  of  Head,7  in 
which  the  movements  of  a  slip  of  the  diaphragm,  the  most  promi- 
nent inspiratory  muscle,  were  recorded,  show  that  this  inhibition 
produced  an  instant  relaxation  of  the  diaphragm.  If  the  vagi 
have  been  frozen  the  relaxation  is  greatly  delayed,  and  even 
after  the  delay  is  at  first  very  imperfect.  The  inhibition  of  inspira- 
tion initiates  an  expiratory  phase,  which  continues  until,  in  its 
turn,  it  also  is  cut  short  by  deflation  to  a  certain  point,  at  which 
the  vagi  transmit  an  influence  which  inhibits  expiration  and 
initiates  the  inspiratory  phase.  It  appears  from  Head's  experi- 
ments that  if  the  vagi  are  frozen  after  the  inspiratory  or  expira- 
tory phase  has  been  initiated,  this  phase  still  continues.  If  with 
vagi  intact  the  breathing  is  partially  obstructed,  inspiration  or 
expiration  is  continued  till  either  act  is  complete.  The  influence 
transmitted  through  the  vagi  initiates  inspiration  or  expiration, 
therefore;  and  the  center  persists  in  the  inspiratory  or  expiratory 
phase  till  the  vagus  gives  the  signal  which  terminates  the  phase 
and  initiates  the  complementary  phase.  The  center  behaves  as  if 
it  always  remembered  the  last  signal;  and  the  analogy  between 
any  act  dependent  on  memory  and  the  duration  of  the  inspiratory 
or  expiratory  phases  of  breathing  is  evident.  We  are  equally 
reminded  of  the  "refractory  period"  in  the  phases  of  cardiac  and 
other  muscular  activity. 

Where  the  "chemical"  regulation  of  the  respiratory  center 
exerts  its  preponderating  influence  is  in  determining  the  extent 
to  which  inflation  or  deflation  of  the  lungs  must  extend  in  order 
that  the  Hering-Breuer  stimuli  should  be  effective,  and  also  the 
vigor  and  consequently  the  rapidity  of  the  inspiratory  and  expira- 
tory movements.  Thus  an  increased  CO2  stimulus  causes  increased 
depth  of  breathing,  since  a  greater  inflation  or  deflation  of  the 
lungs  is  required  before  the  stimulus  of  inflation  or  deflation 
becomes  effective.  At  the  same  time  the  movements  of  the  chest 
wall  become  more  rapid,  so  that  the  frequency  of  breathing  is 
not  diminished  in  consequence  of  the  greater  distances  traveled 
by  the  chest  walls.  The  net  result  is  thus  ordinarily  increase 
in  depth  without  diminution  in  frequency.  But  if  the  frequency 

T  Head,  Journ.  of  Physiol.,  X,  pp.  i  and  279,  1889. 


RESPIRATION  49 

is  diminished  in  consequence  of  voluntary  or  involuntary  inter- 
ference, the  depth  is  correspondingly  increased  owing  to  a  very 
slightly  increased  CO2  stimulus.  This  is  the  explanation  of  why 
the  mean  alveolar  CO2  percentage  remains  so  steady  with  varying 
frequency  of  breathing.  It  is  only,  as  a  rule,  when  there  is  very 
considerable  increase  in  the  breathing  that  there  is  any  material 
increase  in  the  frequency;  and  during  health  the  frequency  is 
hardly  affected  by  moderate  muscular  exertions  or  moderate 
stimulation  by  CO2  in  other  ways.  The  frequency  of  breathing 
is  thus  no  measure  of  the  amount  of  air  breathed;  but  undue 
frequency  of  breathing,  as  will  be  shown  later,  is  a  very  important 
abnormal  sympton. 

The  response  of  the  breathing  to  abnormal  resistance  has  re- 
cently been  investigated  by  Davies,  Priestley,  and  myself.8  For 
recording  the  depth  and  frequency  of  breathing  we  used  the 
recording  "concertina"  described  in  Chapter  VII  (Figure  43). 
For  a  resistance  to  breathing  we  sometimes  used  partly  closed 
taps,  the  effects  of  which  could  be  thrown  in  suddenly  by  closing 
alternative  inspiratory  and  expiratory  air  passages.  In  place  of 
the  taps  we  also  sometimes  employed  cotton  wool  resistances,  as 
with  a  cotton  wool  resistance  the  driving  pressure  varies  directly 
as  the  air  flow,  while  with  a  tap  the  pressure  varies  as  the  square 
of  the  air  flow.  The  pressure  was  measured  with  a  water  ma- 
nometer connected  with  the  tubing  between  the  mouth  and  the 
resistance. 


Figure  15. 

Effects  of  resistance.  In  this  and  subsequent  figures  inspiration  =  upstroke. 
Time  marker  =  10  seconds.  To  read  from  left  to  right. 

It  was  found  that  when  a  resistance  is  thrown  in  the  immediate 
effect  is  a  great  slowing  of  the  breathing.  After  the  next  breath 
the  respirations  become  deeper  and  less  slow,  and  after  several 
breaths  the  breathing  settles  down  to  a  rhythm  in  which  the 
respirations  are  deeper  and  correspondingly  less  frequent.  With 
a  considerable  resistance  the  frequency  is  often  reduced  to  a  fourth 
of  the  normal  rate,  while  the  depth  is  almost  correspondingly  in- 

8  Davies,  Haldane,  and  Priestley,  Journ.  of  PAysiol.,  LIII,  p.  60,  1919. 


50  RESPIRATION 

creased  (Figure  15).  The  explanation  of  this  is  obvious  from  the 
foregoing  account  of  the  physiology  of  the  Hering-Breuer  reflex. 
When  a  resistance  is  thrown  in  deflation  or  inflation  of  the  lungs 
is  slowed,  but  continues  till  the  point  is  reached  at  which  the 
phase  of  respiration  is  reversed  by  the  reflex.  Meanwhile,  how- 
ever, CO2  has  begun  to  accumulate,  so  that  the  next  respiration 
is  not  only  more  vigorous  but  deeper ;  and  the  final  result  is  deeper 
and  less  frequent  respiration. 

When  there  is  no  resistance  to  breathing  the  compensation  of 
diminished  frequency  by  increased  depth  is  almost  perfect,  as 
shown  by  the  experiments  already  quoted  of  Priestley  and  my- 
self; but  when  the  slowing  is  due  to  resistance  the  compensation 
is  less  perfect,  since  the  extra  work  performed  by  the  respiratory 
muscles  implies  a  more  powerful  stimulus  of  CO2  to  the  respira- 
tory center.  Accordingly  the  alveolar  CO2  percentage  rises  quite 
considerably  with  resistance  to  breathing.  The  following  table 
shows  the  rises  observed  by  Davies,  Priestley,  and  myself  with 
varying  resistances. 

Just  as,  in  the  absence  of  resistance  a  very  slight  increase  in  the 
alveolar  CO2  percentage,  and  consequent  slight  increase  in  the 
chemical  stimulus  to  the  respiratory  center,  increases  the  depth 
of  breathing,  so  a  slight  diminution  in  alveolar  CO2  percentage 
diminishes  the  depth.  It  was  recently  discovered  independently  by 
Yandell  Henderson  in  America  and  by  Liljestrand,  Wollin,  and 
Nilsson  in  Sweden  that  if  apnoea  is  first  produced  and  artificial 
respiration  then  carried  out  by  Schafer's  or  one  of  the  other  usual 
methods  the  quantity  of  air  which  enters  the  chest  at  each  artificial 
inspiration  is  only  about  a  third  or  less  of  what  enters  during 
artificial  respiration  when  the  subject  has  simply  suspended  vol- 
untarily his  own  breathing.  With  voluntary  suspension  of  the 
natural  breathing,  moreover,  the  volume  of  air  which  enters  at 
each  artificial  inspiration  varies  (roughly  speaking)  inversely 
as  the  frequency  of  the  artificial  breathing,  so  that  it  is  impossible 
to  produce  a  condition  of  true  apnoea  by  increasing  the  frequency 
of  the  artificial  breathing.  If,  finally,  the  air  artificially  inspired 
contains  an  excess  of  CO2,  the  volume  introduced  by  the  artificial 
respiration  increases  just  as  it  would  with  natural  breathing.  It  is, 
in  fact,  just  as  if  the  subject  were  himself  breathing  naturally  all 
the  time,  in  spite  of  the  undoubted  fact  that  he  has  suspended  his 
natural  breathing. 

These  phenomena  are  completely  intelligible  on  the  theory  that 
the  limits  within  which  inflation  or  deflation  of  the  lungs  inhibits 


RESPIRATION  51 


SUBJECT               ALVEOLAR  CO2               RESISTANCE  IN 

PERCENTAGE                     CM.  OF  H2O 

During     Inspira- 

N  ormal  resistance      tory     Expiratory 

Remarks 

J.  S.  H.              5-40           5-34             4^              1^2 

Slight    cotton-wool   resistance. 

Breathing  slowed 

J.  G.  P.              5-60           5-80             4^              ^A 

Slight    cotton-wool    resistance. 

Breathing  slowed 

H.  W.  D.          5.97          6.24          13                  5 

Heavier  cotton-wool  resistance. 

Breathing  slowed 

5-99           5-93(?)      8                  4 

Lighter  cotton-wool  resistance. 

Breathing  slowed 

6.61 

Lighter  cotton-wool  resistance. 

Breathing  slowed 

6.21 

Lighter  cotton-wool  resistance. 

Breathing  slowed 

6.26 

Lighter  cotton-wool  resistance. 

Breathing  slowed 

7.02          25                14 

Heavy  cotton-wool   resistance. 

Breathing  slowed 

J.  S.  H.             5.4            6.40 

Heavy  cotton-wool  resistance. 

Breathing  quickened 

6.60 

Heavy  cotton-wool  resistance. 

Breathing  about  66 

6.76             ?                  ? 

Resistance    lessened   by  partly 

opening    taps.     Respirations 

about  30 

J.   G.   P.            5-37          5.76             ?                  ? 

Tap     resistance     lessened     by 

partly   opening  taps.    Respi- 

rations about  4 

J.  S.  H.            5.33          6.50             ?                 ? 

Tap     resistance     lessened     by 

partly  opening  taps.    Respi- 

rations about  24 

6.80             ?                 ? 

Tap  resistance  increased.  Res- 

pirations about  40 

52  RESPIRATION 

inspiration  or  expiration  depend  on  the  alveolar  CO2  percentage. 
In  apnoea  a  very  slight  amount  of  inflation  or  deflation  is  suffi- 
cient to  cause  inhibition  of  inspiration  or  expiration.  In  conse- 
quence of  this  the  respiratory  movements  are  nearly  jammed  in 
a  mean  position  during  apnoea  unless  considerable  force  is  ex- 
erted, which  is  not  the  case  with  ordinary  methods  of  artificial 
respiration.  With  a  normal  stimulation  of  the  respiratory  center 
by  CO2  and  a  normal  respiratory  frequency,  the  limits  of  inflation 
or  deflation  at  which  the  Hering-Breuer  inhibition  occurs  are  a 
good  deal  wider,  and  with  a  diminished  respiratory  frequency, 
or  an  increased  percentage  of  CO2  in  the  air  inspired,  the  limits 
are  much  wider  still.  Thus  the  respiratory  center  tends  indirectly 
to  govern  artificial  respiration  unless  the  latter  is  of  a  specially 
vigorous  kind. 

That  the  center  responds,  even  during  apnoea,  with  tonic  con- 
traction of  the  diaphragm  to  deflation  of  the  lungs,  and  with  re- 
laxation to  inflation,  was  clearly  shown  by  Head's  experiments; 
and  the  inspiratory  or  expiratory  pressures  produced  by  the 
diaphragm  and  other  respiratory  muscles  can  easily  be  demon- 
strated in  man.  The  continued  control  of  respiratory  movements 
during  apnoea  or  voluntary  suspension  of  the  breathing,  or  during 
voluntary  variations  in  the  frequency  of  breathing,  is  thus  readily 
intelligible.  In  voluntary  forced  breathing  or  in  forcible  artificial 
respiration,  this  control  is  broken  down.  It  must  not,  however,  be 
assumed  that  because  the  ordinary  gentle  methods  of  human 
artificial  respiration  have  such  a  small  effect  during  ordinary 
apnoea,  the  effect  will  be  equally  small  where  the  suspension  of 
breathing  has  been  caused  by  asphyxiation  or  the  action  of  an 
anaesthetic  or  other  poison.  In  these  cases  the  excitability  of  the 
respiratory  center  to  the  Hering-Breuer  stimuli  is  possibly  as 
much  depressed  as  its  excitability  to  CO2,  in  which  case  the 
artificial  respiration  will  not  be  insufficient. 

The  normal  rate  and  depth  of  breathing  in  any  individual  is  evi- 
dently an  expression  of  the  normal  balance  between  chemical  and 
nervous  stimuli.  The  normal  is  fairly  constant  because  the  balance 
is  a  stable  one.  It  may,  however,  be  greatly  altered  under  abnormal 
conditions,  and  it  can  easily  be  interfered  with  voluntarily. 

It  is  evident  from  the  foregoing  discussion  that  we  cannot 
separate  the  nervous  from  the  "chemical"  control  of  breathing, 
since  each  determines  the  other  at  every  point.  From  too  exclusive 
a  consideration  of  the  nervous  side  of  the  control  it  has  been  sup- 
posed, on  the  one  hand,  that  the  center  is  essentially  automatic  in 


RESPIRATION  53 

its  action,  or  that  its  alternate  inspiratory  and  expiratory  dis- 
charges are,  under  normal  resting  conditions,  determined  simply 
by  alternating  stimuli  transmitted  through  the  vagus  nerves.  On 
the  other  hand  a  too  exclusive  consideration  of  the  chemical  side 
leads  to  the  erroneous  impression  that  the  discharges  of  the  center 
are,  apart  from  occasional  voluntary  or  other  interferences,  de- 
termined in  strength  and  duration  solely  by  chemical  stimuli.  If, 
finally,  we  attempt  to  determine,  one  by  one,  the  "factors"  in  the 
regulation  of  breathing,  the  sum  of  the  supposed  factors  turns 
out  to  be  illusory,  since  no  one  of  them  is  a  constant  quantity.  The 
evaluation  of  each  factor  depends  on  its  varying  relation  to  the 
others. 

The  "respiratory  center"  is  a  small  area  situated  in  the  medulla 
oblongata.  It  has  been  found  that  when  this  area  is  destroyed,  all 
rhythmical  respiratory  movements  cease,  and  that  so  long  as  this 
area  is  intact  and  in  connection  with  any  efferent  nerves  supply- 
ing respiratory  muscles,  discharges  of  the  center  through  these 
nerves  continue,  as  shown  by  the  rhythmical  contractions  of  the 
muscles,  although  all  the  other  nervous  connections  upwards  and 
downwards  have  been  severed. 

It  is  also  now  clear  that  the  activity  of  the  center  depends  upon 
the  composition  of  the  blood  circulating  through  it,  and  not  on 
chemical  stimuli  acting  elsewhere.  If  the  circulation  to  the  medulla 
is  interrupted  by  closure  of  all  the  four  arteries  supplying  it,  so 
that  its  blood  has  time  to  become  venous,  violent  hyperpnoea  re- 
sults, as  Kiissmaul  and  Tenner  showed  about  the  middle  of  last 
century;  and  the  crossed  circulation  experiments  of  Fredericq, 
already  referred  to,  prove  that  either  apnoea  or  hyperpnoea  is 
produced,  according  as  the  blood  supplied  to  the  central  nervous 
system  is  more  aerated  or  less  aerated  in  the  lungs. 

It  has  been  suspected  that  although  the  stimuli  dependent  on 
the  composition  of  the  blood  act  directly  within  the  brain,  nervous 
end-organs  situated  elsewhere  are  also  sensitive  to  these  stimuli, 
so  that  the  corresponding  nerves  convey  impulses  which  play  an 
important  part  in  the  regulation  of  breathing.  It  was,  for  instance, 
believed  by  Traube  that  chemical  stimuli  are  conveyed  directly 
from  the  lungs  by  the  vagus  nerve,  and  others  have  supposed 
that  stimuli  to  increased  breathing  are  conveyed  by  direct  nervous 
paths  from  the  muscles.  This  hypothesis  was  investigated  with 
great  care  by  Geppert  and  Zuntz,9  who  severed  all  the  nervous 
connections  between  actively  working  muscles  and  the  medulla, 

'Geppert  and  Zuntz,  Pfliiger's  Archiv,  XLII,  pp.  195,  209,  1888. 


54  RESPIRATION 

and  found  that  the  respiratory  response  to  increased  muscular 
work  was  the  same  as  before,  but  was  entirely  absent  if  the  circu- 
lation from  the  working  muscles  was  interrupted.  Similarly  they 
found  that  severance  of  the  nervous  connection  between  the  lungs 
and  the  center  did  not  affect  the  response.  Lorrain  Smith  and  I 
found,  similarly,  that  when  air  containing  about  20  per  cent  of 
CO2  was  supplied  to  a  rabbit  there  was  no  difference  in  the  time 
required  for  the  onset  of  hyperpnoea  after  the  vagi  were  cut. 

No  definite  anatomical  group  of  nerve  cells  has  been  defined  at 
the  position  occupied  by  the  respiratory  center;  and  the  exact 
meaning  which  ought  to  be  attached  to  the  expression  "respira- 
tory center"  is  still  doubtful.  It  seems  pretty  clear,  however,  that 
the  center  is  at  about  the  position  which  is  sensitive  to  the  chem- 
ical respiratory  stimuli.  To  judge  from  analogy  the  sensitive 
elements  are  probably  not  the  bodies  of  nerve  cells,  but  end- 
organs  or  arborizations.  The  central  paths  for  the  innervation  of 
inspiratory  and  expiratory  movements  must  also  be  different,  but 
in  what  sense  the  center  itself  is  double  is  still  obscure.  Its  excita- 
tion by  chemical  stimuli  depends  more  upon  the  character  of  the 
blood  supplied  to  it  than  on  substances  generated  by  its  own  local 
metabolism.  Thus  the  temporary  diminution  of  blood  supply  in 
fainting  does  not  produce  the  same  prompt  effect  on  the  center  as 
changes  in  the  arterial  blood  owing  to  imperfect  aeration  in  the 
lungs.  In  this  respect  the  center  is  very  well  suited  to  fulfill  the 
function  of  taking  a  part  in  controlling  the  quality  of  the  general 
arterial  blood  supply  of  the  body.  The  amount  of  arterial  blood 
supplied  is  controlled  in  other  ways. 

Like  other  parts  of  the  central  nervous  system,  the  respiratory 
center  can  easily  be  fatigued;  and,  as  will  be  explained  later, 
fatigue  of  the  respiratory  center  is  of  great  importance  in  practical 
medicine.  Fatigue  of  respiration  was  recently  studied  by  Davies, 
Priestley,  and  myself,  and  its  phenomena  described  in  the  paper 
already  referred  to.  The  fatigue  was  produced  by  breathing 
against  a  resistance,  the  breathing  being  also  increased  at  the 
same  time,  if  necessar)',  by  muscular  exertion.  The  resistance  was 
produced  by  cotton  wool  in  the  manner  already  described. 

So  long  as  the  center  is  functioning  normally  it  responds  to  the 
resistance,  in  the  manner  indicated  above,  by  producing  a  constant 
slow  and  deep  type  of  breathing.  When,  however,  the  resistance 
is  excessive  and  continued  for  some  time,  the  breathing  becomes 
progressively  shallower  and  more  frequent.  At  the  same  time  the 
alveolar  ventilation  becomes  less  and  less  effective,  until  at  last 


RESPIRATION 


55 


asphyxial  symptoms  begin  to  develop.  Figure  16  is  a  tracing 
which  shows  this  change.  Figure  1 7  shows  a  similar  change  pro- 
duced, not  by  resistance  alone,  but  by  the  combined  effects  of 
resistance  and  the  increased  breathing  due  to  muscular  work. 


IllJimHilliiiiih. 


Ron 


iRo// 


Figure  16. 
Effects  of  heavy  resistance.  To  read  from  left  to  right. 


fR.dwr.Jf 


Figure  17. 
Effects  of  resistance  and  gentle  work.  To  read  from  left  to  right. 

It  will  be  shown  later  that  even  a  slight  deficiency  in  the  oxy- 
genation  of  the  arterial  blood  favors  greatly  the  development  of 
fatigue  symptoms  in  the  respiratory  center.  But  addition  of  oxy- 
gen to  the  air  does  not  prevent  the  development  of  fatigue  due 
simply  to  great  extra  work  thrown  on  the  respiratory  center.  When 
the  breathing  is  quite  free,  and  the  oxygenation  of  the  blood 
normal,  fatigue  does  not  at  all  readily  show  itself,  and  greatly 
increased  breathing  goes  on  in  a  normal  manner  over  long  periods. 
During  muscular  exertion,  however,  as  will  be  shown  later,  the 
oxygenation  of  the  blood  may  become  impaired,  in  which  case 
fatigue  of  the  breathing  may  easily  show  itself,  so  that  the  subject 
becomes  in  a  literal  sense  "short  of  breath,"  since  each  breath 
is  short. 


56  RESPIRATION 

During  the  war  cases  were  very  common  of  what,  according  as 
one  nervous  symptom  or  another  was  most  prominent,  was  desig- 
nated as  "chronic  gas  poisoning,"  "soldier's  heart,"  "disordered 
action  of  the  heart,"  "neurasthenia,"  etc.  In  these  cases  "shortness 
of  breath"  on  exertion  was  a  common  and  prominent  symptom. 
Their  breathing  was  investigated  by  Meakins,  Priestley,  and  my- 
self10 and  we  found  a  marked  deviation  from  normality  in  its  reg- 
ulation. In  many  of  these  persons  the  frequency  of  the  breathing 
was  very  abnormally  increased  during  rest,  and  in  nearly  all  there 
was  on  exertion  a  quite  abnormal  increase  of  frequency,  with  a 
corresponding  reduction  of  the  normal  increase  of  depth.  The 
symptoms  were  thus  the  same  as  those  of  fatigue  of  the  respira- 
tory center,  and  on  extra  exertion  these  patients  were  liable  to 
lose  consciousness  with  asphyxial  symptoms,  just  as  in  ordinary 
overfatigue  of  the  center.  Another  prominent  symptom  was  that 
the  patients  were  unable  to  hold  a  deep  breath  for  anything  like 
a  normal  period,  even  if  they  were  given  oxygen  to  help.  Many  of 
them  were  also  subject,  particularly  at  night,  to  attacks  of  rapid 
shallow  breathing  with  a  sense  of  impending  suffocation. 

The  condition  of  the  breathing  in  these  patients  was  evidently 
such  as  would  be  produced  by  an  abnormal  increase  in  the  readi- 
ness with  which  the  Hering-Breuer  reflex  is  elicited,  and  we 
therefore  described  the  respiratory  condition  as  one  of  "reflex  re- 
striction" in  the  depth  of  breathing.  At  the  time  we  were  not 
aware  of  the  symptoms  of  fatigue  of  the  respiratory  center.  In  the 
condition  of  fatigue  the  shallow  and  rapid  breathing  is  just  what 
would  result  from  an  increase  in  the  strength  of  the  Hering- 
Breuer  reflex,  and  a  similar  apparent  exaggeration  of  this  reflex 
is  present,  as  already  seen  in  connection  with  the  results  of  artificial 
respiration,  in  the  condition  of  apnoea.  In  view,  therefore,  of  all 
the  facts  relating  to  the  respiratory  movements  in  fatigue,  apnoea, 
and  neurasthenia,  it  seems  probable  that  the  apparent  increased 
strength  in  the  Hering-Breuer  reflex  is  due  to  a  diminution  in 
the  persistency  of  the  individual  inspiratory  and  expiratory  dis- 
charges from  the  center,  rather  than  to  any  real  increase  in  the 
inhibitory  Hering-Breuer  discharges  up  the  vagus  nerves.  It  is 
thus  only  the  weakness  of  the  center  that  enables  the  Hering- 
Breuer  reflex  to  gain  the  upper  hand. 

If  we  apply  the  same  general  conception  to  the  other  exag- 

10  Haldane,  Meakins,  and  Priestley,  Reports  of  the  Chemical  Warfare  Meciical 
Committee,  No.  5,  Reflex  Restrictions  of  Breathing,  1918,  and  No.  n,  Chronic 
Cases  of  Gas  Poisoning,  1918;  also  Journ.  of  Physiol.,  LII,  p.  433. 


RESPIRATION  57 

gerated  reflexes  and  general  failure  of  nervous  coordination  in 
"neurasthenia,"  fatigue,  and  "shock,"  we  seem  to  render  these 
conditions  more  intelligible.  Thus  the  great  general  nervous  ir- 
ritability, exaggeration  of  circulatory  reflexes,  tendency  to  sweat- 
ing, and  occasional  instability  of  temperature,  as  observed  in 
"neurasthenia/'  are  probably  analogous  to  the  exaggerated  re- 
flex restriction  in  the  depth  of  breathing  and  the  inability  to  hold 
a  breath.  All  these  symptoms  seem  to  be  due  to  what  Hughlings 
Jackson  called  "release  of  control." 

In  the  causation  of  military  neurasthenia  the  nervous  over- 
strain of  war,  and  the  shocks  to  the  nervous  system  in  connection 
with  various  incidents  of  warfare  and  gross  bodily  injuries  had 
evidently  played  a  prominent  part;  but  it  was  equally  evident 
that  infections  of  different  sorts  were  also  in  part  responsible  for 
the  condition,  the  nervous  system  being  apparently  weakened  by 
toxic  influences.  In  the  same  way  ordinary  fatigue  of  the  respira- 
tory center  or  other  parts  of  the  nervous  system  may  be  due  not 
merely  to  extra  work,  but  also  partly  to  want  of  oxygen  (as  will 
be  shown  later) ,  or  to  other  chemical  influences.  Neurasthenia  may 
thus  be  regarded  as  only  a  more  lasting  and  persistent  form  of 
ordinary  fatigue  or  exhaustion.  It  will  be  shown  later  that  a  very 
important  secondary  effect  of  the  shallow  breathing  characteris- 
tic of  neurasthenia  or  fatigue  of  the  respiratory  center  is  im- 
perfect oxygenation  of  the  blood. 

The  readiness  with  which  a  given  resistance  to  breathing  pro- 
duces signs  of  fatigue  of  the  breathing  varies  greatly  in  different 
individuals.  In  some  persons  a  comparatively  small  resistance 
suffices  to  produce  shallow  breathing  and  rapid  exhaustion  of  the 
respiratory  center,  though  in  other  quite  healthy  persons  a  very 
considerable  resistance  is  needed.  Men  with  symptoms  of  neu- 
rasthenia are,  as  might  be  expected,  particularly  sensitive  to  re- 
sistance. This  matter  is,  of  course,  important  in  connection  with 
the  design  of  respirators,  etc.  A  respirator  causing  any  consider- 
able resistance  may  easily  disable  a  man  for  muscular  exertion. 

The  threshold  alveolar  CO2  pressure  at  which  the  respiratory 
center  begins  to  be  excited  may  be  altered  by  various  abnormal 
conditions  which  will  be  discussed  further  in  later  chapters.  The 
threshold  may  be  lowered  by  want  of  oxygen  or  by  the  presence 
in  the  blood  of  an  abnormally  low  proportion  of  available  alkali, 
or  by  certain  drugs,  including,  as  Yandell  Henderson11  has  pointed 

11  Yandell  Henderson  and  Scarbrough,  Amer.  Journ.  of  Physiol.,  XXVI,  p. 
279,  1910. 


58  RESPIRATION 

out,  ether  in  low  concentrations,  or  by  massive  afferent  nervous 
stimuli.  On  the  other  hand  the  threshold  is  raised  by  such  anaes- 
thetics as  chloroform,  morphia,  or  chloral;  and  under  their  influ- 
ence the  alveolar  CO2  pressure  is  raised12  and  the  breathing  is 
commonly  so  much  diminished  that  the  arterial  blood  becomes 
markedly  blue.  These  facts  are  of  great  importance  in  connection 
with  the  use  of  anaesthetics.  Henderson  showed  also  that  morphia 
affects  the  chemical  more  than  the  afferent  threshold  of  the  res- 
piratory center.  Rise  of  body  temperature  has  a  marked  effect  in 
lowering  the  threshold.13 

u  Collingwood  and  Buswell,  Journ.  of  Physiol.  (Proc.  Physiol.  Soc.),  XXXV, 
p.  xxxiv,  and  XXXVI,  p.  xxi,  1907. 

13  Haldane,  Journ.  of  Hygiene,  V,  p.  503,  1905;  see  also  Haggard,  Journ.  of  Biol. 
Chem.  XLIV,  p.  131,  1920. 


CHAPTER  IV 
The  Blood  as  a  Carrier  of  Oxygen. 

THE  evidence  has  already  been  referred  to  that  nearly  all  the 
available  oxygen  in  the  blood  is  present  in  the  form  of  a  chemical 
compound  with  the  haemoglobin  of  the  red  corpuscles,  and  that 
this  compound  has  the  remarkable  property  of  dissociating  with 
fall  in  the  partial  pressure  of  oxygen,  at  the  same  time  changing 
its  color  from  bright  scarlet  to  a  dark  purple.  It  dissociates  com- 
pletely when  the  oxygen  pressure  is  reduced  to  zero,  and  the 
readiness  with  which  the  dissociation  occurs  is  dependent  on 
temperature  and  other  conditions  which  will  be  discussed  below. 
It  is  contained  in  the  corpuscles  to  the  extent  of  about  30  per  cent 
of  their  weight,  and  on  liberation  from  them  it  can  be  crystallized 
out  with  comparative  ease  by  the  help  of  cold  and  of  substances 
which  diminish  its  solubility.  There  is  considerable  variation  in 
the  form  of  the  crystals  obtained  from  the  blood  of  different 
animals. 

To  what  extent,  and  in  what  directions,  the  elementary  composi- 
tion of  haemoglobin  varies  is  not  yet  definitely  known;  but  the 
haemoglobin  of  birds  has  been  found  to  contain  phosphorus,  while 
none  is  present  in  the  haemoglobin  of  mammals.  Iron  is  always 
present.  A  given  amount  of  blood,  whether  or  not  the  corpuscles 
have  been  dissolved  and  the  haemoglobin  liberated  and  diluted, 
takes  up,  on  saturation  with  air  at  room  temperature,  a  perfectly 
fixed  and  definite  amount  of  oxygen  in  chemical  combination.  No 
further  measurable  quantity  is  taken  up,  except  in  simple  physical 
solution,  on  saturation  with  oxygen.  An  exactly  equal  volume  of 
carbon  monoxide  or  nitric  oxide  is  taken  up  in  combination  in 
presence  of  either  of  these  gases.  There  is  no  shadow  of  doubt  that 
the  combination  is  a  chemical  one,  though  some  extraordinary 
attempts,  based  on  ignorance  of  well-ascertained  facts,  have  re- 
cently been  made  to  explain  the  combinations  of  oxygen  and  CO2 
in  blood  as  due  to  adsorption. 

Haemoglobin  not  only  enters  into  dissociable  chemical  combina- 
tions with  oxygen,  carbon  monoxide  and  nitric  oxide,  but  also  in 
presence  of  various  oxidizing  agents,  such  as  ferricyanides  or 
chlorates,  or  very  weak  acids,  etc.,  when  oxygen  is  also  present, 
passes  into  a  modification  called  by  Hoppe  Seyler  methaemoglobin. 


60  RESPIRATION 

This  substance,  which  crystallizes  in  a  similar  form  to  oxyhaemo- 
globin  but  has  a  dull  brown  color  in  acid  solution  and  a  brownish 
red  color  in  alkaline  solution,  was  found  by  Hiifner  to  take  up  in 
its  formation  from  haemoglobin  just  as  much  oxygen  as  oxy- 
haemoglobin ;  but  the  oxygen  is  not  given  off  in  a  vacuum.  On  the 
other  hand  it  yields  its  oxygen  much  more  rapidly  to  a  reducing 
agent  than  oxyhaemoglobin  or  free  oxygen  does,  and  is  thus  an 
oxidizing  agent  of  some  activity.  Thus  if  a  drop  of  ammonium 
sulphide  solution  is  mixed  with  a  solution  of  methaemoglobin  in 
the  absence  of  free  oxygen  the  methaemoglobin  is  instantly  re- 
duced to  haemoglobin,  as  shown  by  the  change  of  color  and  spec- 
trum. But  if  free  oxygen  is  present  the  color  and  spectrum  of 
oxyhaemoglobin  appear,  since  the  ammonium  sulphide  combines 
far  more  slowly  with  free  oxygen,  or  with  the  combined  oxygen 
of  oxyhaemoglobin,  so  that  the  haemoglobin  formed  instantly 
from  the  methaemoglobin  is  able  to  combine  with  the  free  oxygen 
and  remain  for  a  long  time  as  oxyhaemoglobin. 

While  investigating  the  action  of  poisons  which  form  met- 
haemoglobin in  the  living  body  I  noticed  that  when  ferricyanide 
and  certain  other  reagents  act  on  oxyhaemoglobin  to  form  methae- 
moglobin fine  bubbles  are  liberated,  and  on  further  investigation 
the  liberated  gas  was  found  to  be  oxygen.1  I  then  measured  ac- 
curately the  liberated  oxygen,  and  found  that  the  volume  of  oxy- 
gen liberated  by  ferricyanide  from  blood  agrees  exactly  with  the 
volume  liberated  by  the  mercurial  pump  from  combination  in  the 
blood.  Ferricyanide  also  liberates  carbon  monoxide  from  its  com- 
bination with  haemoglobin,  and  the  volume  liberated  corresponds 
with  the  volume  of  oxygen  liberated  by  a  corresponding  quantity 
of  oxyhaemoglobin.  The  following  figures  were  obtained. 


Combined  gas  in  cc.  liberated,  from 
the  haemoglobin  of  100  cc.  of  blood 
and  measured  dry  at  Q°C  and  760  mm. 

By  blood  pump  alone  from  blood  saturated  with  air  18.18 

By  ferricyanide  from  blood  saturated  with  air  18.20 

By  ferricyanide  from  blood  saturated  with  CO  18.07 


From  their  behavior,  it  appears  that  oxyhaemoglobin  and  CO- 
haemoglobin  are  molecular  compounds  in  which  the  molecules  of 

1Haldane,  Journ.  of  Physiol.,  XXII,  p.  298,  1898. 


RESPIRATION  6l 

gas  are  directly  combined  as  such  with  the  molecules  of  haemo- 
globin, just  as  molecules  of  water  are  combined  with  molecules  of 
a  salt  or  other  substance  to  form  hydrate  molecules.  In  methaemu- 
globin,  on  the  other  hand,  the  atoms  in  the  molecules  of  oxygen 
which  enter  into  combination  are  separately  combined  just  as  in 
ordinary  chemical  compounds  containing  oxygen.  When  the 
oxidation  of  haemoglobin  to  methaemoglobin  occurs  the  new 
molecule  formed  loses  its  capacity  for  forming  the  molecular 
compounds  oxyhaemoglobin  and  carboxyhaemoglobin.  In  conse- 
quence of  this  the  molecular  oxygen  and  carbon  monoxide  are 
liberated  from  oxyhaemoglobin  or  carboxyhaemoglobin  by  the 
action  of  ferricyanide,  and  can  be  measured  with  the  greatest  ac- 
curacy in  the  gaseous  form  by  a  simple  method  which  I  described 
in  1900  (see  Appendix).2 

The  ferricyanide  method  afforded  a  ready  means  of  measuring 
directly  the  gas  combined  in  the  molecular  form  with  haemo- 
globin, and  for  this  purpose  replaced  the  complicated  procedure 
and  involved  calculations  required  when  the  mercurial  pump 
was  used.  One  of  the  first  discoveries  made  with  the  new  method 
was  that  the  coloring  power  of  haemoglobin  or  any  one  of  its 
molecular  compounds  with  gases  varies  exactly  as  its  capacity  for 
combining  with  gas.  Hence  the  "oxygen  capacity"  of  the  haemo- 
globin in  blood — in  other  words  its  power  of  fulfilling  its  physio- 
logical function  of  carrying  oxygen — can  be  measured  easily  by 
means  of  a  reliable  colorimetric  method.3  The  following  table 
(p.  62)  shows  the  results  we  obtained  on  this  point. 

That  oxygen  capacity  and  depth  of  color  run  parallel  also  in 
various  anaemias  and  other  pathological  conditions  was  shown 
by  Morawitz  ;4  and  Douglas5  showed  that  even  during  the  rapid 
regeneration  of  haemoglobin  after  loss  of  blood  this  also  holds. 

At  the  time  when  the  ferricyanide  method  was  introduced  there 
existed  several  well-known  forms  of  "haemoglobinometer."  Of 
these  the  apparatus  of  the  late  Sir  William  Gowers  was  by  far  the 
most  convenient.  In  his  method  20  cubic  millimeters  of  blood, 
obtained  from  a  prick  of  the  skin,  are  introduced  into  a  small 
graduated  tube  and  diluted  with  water  until  the  depth  of  color 
is  the  same  as  that  of  a  standard  solution  of  picrocarmine  in  an- 
other similar  tube.  The  depth  of  color  of  the  picrocarmine  solution 

a  Haldane,  Journ.  of  Phystol.,  XXV,  p.  295,  1900. 

*  Haldane  and  Lorrain  Smith,  Journ.  of  Physiol.,  XXV,  p.  331,  1900. 

4  Morawitz  and  Rohmer,  Deutsch.  Arch.  f.  kUn.  Med.,  XCIII,  p.   223,   1908. 

5  Douglas,  Journ.  of  Physiol.,  XXXIX,  p.  453,  1910. 


62 


RESPIRATION 


is  that  of  normal  human  blood  diluted  to  i/iooth;  and  the 
graduated  tube  gives  the  strength  of  color  of  the  blood  under 
examination  in  terms  of  this  normal  standard.  One  defect  of  the 
method  was  that  the  picrocarmine  standard  is  not  permanent, 
and  another  that  the  color  of  the  picrocarmine  solution  is  not  the 


OXYGEN  CAPACITY 
PER  100  CC. 

Ferricyanide               Colortmetric 
method                          method 

PERCENTAGE 
DIFFERENCE  IN 
RESULT  BY 
COLORIMETRIC 
METHOD 

Ox  blood                18.51 

18.42 

—0.5 

15.05 

15 

•33 

+  1.9 

20.29 

19.85 

2.2 

15.04 

15 

17 

+0.9 

Horse  blood          18.37 

18.39 

+0.1 

Ox  blood               19.75 
19.90 

$                          20.00 

+0.9 

18.94 

18.94 

+0.0 

Rabbit's  blood      14.62 

\ 

—  O.  I 

14-55. 

) 

Sheep's  blood        17.44 

17- 

30 

—0.8 

17.44 

Ox  blood               21.50 

21.42 

—  0.4 

21.55 

16.16 

16.06 

—0.6 

Human  blood        2  1  .08 

21.27 

+0.9 

Mean         18.07 

18 

.06 

—0.055 

same  spectrally  as  that  of  the  blood  solution.  As  a  consequence  of 
this  both  the  depth  and  the  quality  of  the  tints  of  the  two  solutions 
are  differently  affected  by  variations  in  the  quality  of  the  light  at 
the  time  of  using  the  instrument.  Thus  if  the  tints  agree  at  one  time 
of  day  they  may  be  different  at  another;  and  in  ordinary  artificial 
light  the  results  given  are  totally  different  from  the  results  by 
daylight.  Moreover,  in  consequence  of  individual  differences  in 
vision,  a  color  match  for  one  person  is  not  the  same  as  that  for 
another  person,  even  in  the  same  light.  To  remedy  these  defects  I 
substituted  for  the  picrocarmine  a  one  per  cent  solution  of  blood 
of  the  average  oxygen  capacity  of  the  blood  of  adult  men  (18.5 


RESPIRATION  63 

cc.  of  oxygen  per  100  cc.  of  blood) ,  and  introduced  other  improve- 
ments.6 

In  the  presence  of  free  oxygen  haemoglobin  is  a  very  unstable 
substance,  and  soon  decomposes,  owing  to  the  action  of  bacteria, 
etc. ;  but  in  the  absence  of  oxygen  the  color  of  haemoglobin  is  per- 
fectly stable,  and  this  is  also  the  case  for  carboxyhaemoglobin.  The 
standard  solution  was  therefore  saturated  with  carbon  monoxide 
in  the  absence  of  oxygen,  and  in  this  form  is  permanent.  The  blood 
under  examination  is  also  saturated  with  carbon  monoxide  by 
contact  with  coal  gas  or  a  little  carbon  monoxide.  The  two  solu- 
tions are  thus  spectrally  the  same.  With  these  improvements  the 
Gowers  haemoglobinometer  became  an  extremely  accurate  instru- 
ment for  ascertaining  the  oxygen  capacity  of  blood,  and  the  ac- 
curacy of  any  particular  instrument  could  be  controlled  at  once 
by  the  ferricyanide  method.  Certain  ever-recurring  criticisms  of 
the  instrument  are  almost  entirely  based  on  want  of  acquaintance 
with  the  physiological  principles  of  colorimetric  methods,  or  of 
the  chemical  facts  on  which  the  method  is  based.  A  detailed  de- 
scription of  the  method  will  be  found  in  the  Appendix. 

The  percentage  oxygen  capacity  (or  haemoglobin  percentage) 
in  the  blood  varies  quite  appreciably  from  hour  to  hour  and  day 
to  day,  according  as  the  total  volume  of  the  blood  varies  from  ad- 
dition or  withdrawal  of  liquid.  There  are  also  variations  associ- 
ated with  age  and  sex ;  and  pathological  variations  may  be  very 
marked  and  significant.  As  regards  age  and  sex  I  found  the  follow- 
ing average  relative  figures  for  the  percentage  oxygen  capacity 
of  the  blood. 

Men  18.5 

Women  16.5 

Children  16.1 

It  has  been  known  for  long  that  when  an  oxyhaemoglobin 
solution  is  overheated  or  treated  with  various  simple  reagents  the 
oxyhaemoglobin  decomposes  into  a  coagulated  protein  and  a 
deeply-colored  brown  substance  soluble  in  alcohol  and  certain 
other  solvents,  and  known  as  haematin.  The  haematin  contains  8.7 
per  cent  of  iron,  and  the  coagulated  protein  is  free  from  iron.  To 
the  haematin  the  formula  C34H34N6O5Fe  has  been  assigned.  By 
the  action  of  reducing  agents  the  haematin  loses  oxygen  and 
changes  to  a  purple  color,  with  a  corresponding  change  of  spec- 
trum, described  by  Stokes  at  the  same  time  as  he  described  the 

8  Haldane,  Journ.  of  Physiol.,  XXVI,  p.  497. 


64  RESPIRATION 

spectra  of  oxyhaemoglobin  and  haemoglobin.  To  this  reduced 
haematin  Hoppe  Seyler  gave  the  very  suitable  name  haemo- 
chromogen,  as  he  believed  it  to  be  the  parent  substance  of  the  color 
of  haemoglobin  and  its  varied  derivatives.  Thus  we  can  regard 
haemoglobin  as  a  compound  of  haemochromogen  with  a  protein, 
also  haematin  as  an  oxygen  compound  of  haemochromogen,  while 
compounds  of  haemochromogen  with  carbon  monoxide  and  nitric 
oxide  are  also  known. 

This  conception  is  confirmed  by  the  fact  that  the  oxygen  ca- 
pacity of  haemoglobin  varies  as  its  coloring  power,  and  by  another 
still  more  recently  established  fact.  Till  a  few  years  ago  it  still 
seemed  very  doubtful  whether  there  is  a  fixed  and  definite  rela- 
tionship between  the  iron  in  haemoglobin  and  its  oxygen  capacity; 
and  Bohr7  thought  that  he  had  obtained  evidence  of  the  existence 
of  marked  variations  in  the  relation  between  iron  and  oxygen 
capacity ;  and  that  this  relation  differs  in  arterial  and  venous 
blood.  The  doubts  on  this  subject  turned  round  the  reliability  of 
the  methods  of  determining  iron.  But  in  1912  Peters,  using  a  new 
and  very  reliable  method  of  iron  determination,  found  that  there 
is  a  fixed  and  simple  relationship  between  the  oxygen  capacity  and 
iron,  one  molecule  of  combined  oxygen  corresponding  to  one 
atom  of  iron.8 

Still  other  considerations  point  in  the  same  direction.  When  we 
examine  the  colors  and  spectra  of  the  various  direct  derivatives 
of  haemoglobin  and  haemochromogen  a  striking  general  cor- 
respondence emerges.  Methaemoglobin  and  haematin  have  very 
similar  colors  and  spectra,  which  differ  in  a  more  or  less  similar 
manner  in  acid  or  alkaline  solutions,  and  give  a  similar  red  color 
and  corresponding  spectrum  on  addition  of  hydrocyanic  acid. 
With  carbon  monoxide  haemochromogen  gives  the  same  color 
and  spectrum  and  takes  up  the  same  volume  of  carbon  monoxide 
as  haemoglobin.  With  the  nitric  oxide  compounds  there  appears 
also  to  be  a  correspondence.  Thus  I  found  that  the  red  color  of 
raw  salted  meat  is  due  to  the  presence  of  NO-haemoglobin, 
formed  by  the  action  on  haemoglobin  of  the  reduction  product  of 
the  niter  which  is  mixed  with  the  salt;  and  the  color  is  still  red 
after  the  meat  is  cooked  and  the  NO-haemoglobin  broken  up  to 
yield  a  haemochromogen  compound  on  heating.  NO-haemoglobin 
is  also  found  post  mortem  in  poisoning  by  nitrites.  Between 
haemoglobin  and  haemochromogen  there  is  also  more  or  less  of 

7  Bohr,  Nagel's  Handbuch  der  Physiologie,  I,  p.  95,   1905. 

8  Peters,  Journ.  of  Physiol.,  XLIV,  p.  131,  1912. 


RESPIRATION  65 

correspondence;  but  oxyhaemochromogen,  the  molecular  oxygen 
compound  of  haemochromogen,  is  missing,  and  it  seems  that 
haematin  is  so  readily  formed  by  haemochromogen  in  the  pres- 
ence of  oxygen  that  oxyhaemochromogen  cannot  exist.  Figure  18 
shows  the  positions  of  the  absorption  bands  in  the  spectra  of  NO- 
haemoglobin  and  NO-haemochromogen. 

C  D  E     b  F 


Figure  18. 

i.  Nitric  oxide  haemoglobin.  2.  Oxyhaemoglobin.  3.  Carbonic 
oxide. haemoglobin.  4.  Nitric  oxide  haemochromogen.  5.  Obtained 
by  action  of  nitrous  acid  on  haematin. 

If  haemochromogen  has  been  formed  from  haemoglobin  by 
the  action  of  acids  or  caustic  alkali  and  heat,  a  substance  possess- 
ing the  spectrum  and  properties  of  natural  haemoglobin  is  gradu- 
ally re-formed  on  neutralization.9  As  proteins  are  greatly  altered 
in  properties  by  heating  with  alkali  it  would  seem  from  this  ob- 
servation that  there  may  be  a  number  of  different  haemoglobins, 
in  which,  though  the  haemochromogen  part  of  the  molecule  is 
the  same  in  all,  the  protein  part  varies.  As  will  be  shown  later, 
there  is  evidence  that  not  only  in  different  species,  but  also  in 
different  individuals  of  the  same  species,  the  protein  part  of  the 
haemoglobin  molecule  varies,  thus  producing  slight  variations  in 
the  properties  of  the  haemoglobin  as  a  carrier  of  gases,  although 
there  is  no  variation  in  the  oxygen  capacity  per  unit  weight  of 
iron  present.  The  haemochromogen  part  of  the  molecule  seems, 
on  the  other  hand,  to  be  constant  in  all  the  different  sorts  of  haemo- 
globin, and  this  brings  about  the  identity  of  the  relations  between 
oxygen  capacity,  coloring  power,  and  percentage  of  iron  in  all 
the  different  varieties  of  haemoglobin,  although  as  regards  other 
properties  haemoglobins  from  different  sources  vary  distinctly. 

9  See  Menzies,  Journ.  of  Phystol.,  XVII,  p.  415,  1895,  and  XLIX,  p.  452,  1915- 


66  RESPIRATION 

The  original  ferricyanide  method  for  determining  the  oxygen 
capacity  of  haemoglobin  was  very  accurate,  but  required  a  good 
deal  of  blood,  and  was  also  slow  on  account  of  the  time  needed 
for  exact  equalization  of  temperature  and  gas  pressures.  Mr. 
Barcroft  was  then  beginning  his  important  series  of  investiga- 
tions on  the  metabolism  of  the  salivary  glands  and  other  organs. 
As  he  required  a  blood-gas  method  suitable  for  very  small  volumes 
of  blood  he  asked  me  whether  the  ferricyanide  method  could  be 
adapted  for  the  purpose,  and  I  designed  an  apparatus  which  we 
jointly  tested  and  described,  and  which  turned  out  so  successfully 
that,  in  one  form  or  another,  it  has  now  almost  displaced  the 
mercurial  blood  pump.10  In  this  apparatus  the  oxygen  combined 
in  the  haemoglobin  of  the  very  small  quantity  of  blood  required 
is  liberated  by  ferricyanide,  and  the  CO2  by  acid.  The  amount  of 
gas  liberated  in  either  case  is  determined,  not  from  the  increase 
in  volume  which  its  liberation  causes,  but  from  the  increase  of 
pressure  when  the  total  volume  of  gas  is  kept  rigorously  constant. 
I  adopted  this  principle  as  the  result  of  much  previous  experience 
in  the  measurement  of  small  differences  in  gas  volumes.  Certain 
causes  of  difficulty  are  eliminated  by  the  pressure  method,  and  by 
the  adoption,  as  in  the  original  ferricyanide  method,  of  a  control 
arrangement  by  which  the  effects  of  changes  in  temperature  and 
barometric  pressure  during  the  experiment  are  eliminated.  Vari- 
ous improvements  in  the  technique  of  collecting  and  sampling 
blood  drawn  directly  from  blood  vessels  were  also  introduced  by 
Mr.  Barcroft. 

This  apparatus  has  been  modified  in  various  ways  by  different 
investigators,  and  some  of  the  modifications  are  improvements. 
Others,  however,  seem  to  me  to  be  the  reverse.  In  the  Appendix 
there  is  a  description  of  a  new  and  much  more  exact  method  in 
which  the  volumes  of  oxygen  and  CO2  are  measured  directly. 

Besides  the  oxygen  chemically  combined  with  haemoglobin, 
the  blood  contains  a  certain  small  amount  of  oxygen  in  simple 
solution.  In  accordance  with  Henry's  law  of  solution  of  gases  in 
liquids  this  amount  varies  with  the  partial  pressure  of  oxygen  in 
the  atmosphere  with  which  the  blood  is  saturated,  which  in  the 
case  of  arterial  blood  in  the  living  body  is  (with  certain  reserva- 
tions discussed  in  Chapters  VII  and  VIII),  the  alveolar  air.  The 
amount  of  oxygen  in  free  solution  can  be  measured  directly  when 
the  haemoglobin  is  by  one  means  or  another  put  out  of  action  in 
respect  to  its  power  of  entering  into  molecular  combination  with 

10  Barcroft  and  Haldane,  Journ.  of  Physiol.,  XXVIII,  p.  232,  1902. 


RESPIRATION  67 

oxygen.  Bohr  found  that  at  body  temperature  2.2  cc.  of  oxygen 
(measured  at  o°  and  760  mm.)  go  into  simple  solution  in  100  cc. 
of  blood  when  the  partial  pressure  of  oxygen  is  one  atmosphere,11 
and  this  is  about  8  per  cent  less  than  dissolves  in  water.  In  the 
alveolar  air  the  partial  pressure  of  oxygen  is  only  about  13  per 
cent  of  an  atmosphere,  and  in  the  mixed  arterial  blood  about  1 1 
per  cent,  or  84  mm.,  of  mercury.  Hence  the  amount  of  free  oxygen 
dissolved  in  the  100  cc.  of  the  arterial  blood  of  a  man  is  only  about 
0.24  cc.  (measured  at  o°C.  and  760  mm.  pressure)  whereas 
about  17.4  cc.  are  present  in  combination  with  haemoglobin,  as 
will  be  shown  below.  It  is  evident,  however,  that  the  amount  in 
free  solution  is  of  great  importance;  it  depends  upon  the  partial 
pressure  of  oxygen  in  the  atmosphere  with  which  the  blood  is  in 
equilibrium;  and,  as  already  pointed  out,  Paul  Bert  found  that 
the  physiological  action  of  oxygen  and  of  any  other  gas  depends 
upon  its  partial  pressure  in  this  atmosphere. 

From  the  standpoint  of  physical  chemistry  the  "partial  pres- 
sure" of  a  gas  in  solution  is  simply  the  vapor  pressure  of  the  dis- 
solved gas,  i.e.,  its  tendency  to  pass  out  of  the  solvent  at  any  free 
surface,  or  the  gas  pressure  which  will  just  balance  this  tendency 
so  that  the  amount  of  gas  in  solution  neither  increases  nor  de- 
creases. But  the  vapor  pressure  of  a  substance  in  solution,  or  of  the 
solvent  itself,  varies  directly,  as  I  showed  in  a  recent  paper,12 
with  the  diffusion  pressure  of  the  substance  in  solution.  Hence 
vapor  pressure  is  a  direct  index  of  diffusion  pressure;  and  this  is 
the  reason  why  the  partial  pressure  of  a  gas  in  solution  is  of  so 
great  importance.  It  is  owing  to  differences  in  diffusion  pressure 
that  water  or  substances  dissolved  in  it  tend,  independently  of 
active  "secretory"  processes,  to  pass  in  one  direction  or  another 
in  the  living  body  or  outside  it.  For  instance,  when  water  passes 
through  a  semi-permeable  membrane  into  a  solution  of  sugar  or 
salt,  this  is  because  the  diffusion  pressure  of  the  pure  water  is 
greater  than  that  of  the  diluted  water  in  the  sugar  or  salt  solution. 
Van't  Hoff's  brilliant  discovery  that  there  is  a  connection  between 
the  fundamental  "gas  laws"  and  the  phenomena  of  osmotic  pres- 
sure was  unfortunately  marred  by  his  failure  to  interpret  either 
the  connection  or  the  experimental  facts  correctly.  As  a  conse- 
quence, osmotic  pressure  and  diffusion  pressure  were  either  com- 
pletely misinterpreted  or  confused  with  one  another.  There  seems 
now  to  be  no  doubt  that  it  is  the  diffusion  pressures,  and  not  the 

11  Bohr,  Nagel's  Hancibuch  der  Physiol.,  I,  p.  62,  1905. 
19  Haldane,  Bio-Chemical  Journal,  XII,  p.  464,  1918. 


68  RESPIRATION 

mere  concentration  of  substances  in  the  body,  that  are  of  physio- 
logical importance.  To  illustrate  this  distinction,  the  concentra- 
tion of  water  in  blood  is  much  less  than  in  a  two  per  cent  solution 
of  sodium  chloride ;  but  the  diffusion  pressure  of  water  in  the  blood 
is  much  greater  than  in  the  salt  solution.  Hence  water  will  pass 
from  the  blood  into  salt  solution.  Similarly  carbonic  acid  probably 
passes  by  diffusion  from  the  muscular  substance  into  the  blood 
although  the  concentration  of  free  carbonic  acid  in  the  muscle  is 
less  than  in  the  blood. 

Paul  Bert's  conclusion  that  it  is  the  partial  pressure  of  a  gas 
which  is  of  importance  as  regards  its  physiological  action  can  thus 
be  extended  to  every  other  substance  present  in  the  living  body, 
not  excepting  water.  The  partial  pressure  of  a  dissolved  gas  is  of 
decisive  importance  because  the  gaseous  partial  pressure,  or  vapor 
pressure,  is  an  index  of  the  diffusion  pressure  of  a  substance  in 
solution ;  but  where  the  gaseous  partial  pressure  is  so  low  that  it 
cannot  be  measured,  we  must  have  recourse  to  other  indices  of  the 
diffusion  pressure. 

It  has  been  shown  how  important  are  the  gas  pressures  in  al- 
veolar air.  But  the  gas  pressures  of  the  blood  in  the  systemic 
capillaries  are  of  still  more  fundamental  importance.  It  is  clear 
that  in  order  to  understand  how  the  oxygen  pressure  of  the  blood 
is  regulated  we  must  know  the  connection  between  dissociation  of 
the  oxyhaemoglobin  of  blood  and  fall  in  oxygen  pressure.  In  other 
words  we  must  know  what  is  called  the  dissociation  curve  of  oxy- 
haemoglobin in  blood. 

The  history  of  the  growth  of  knowledge  on  this  subject  is  some- 
what curious.  Paul  Bert13  made  some  rough  determinations  with 
the  pump  of  the  amounts  of  oxygen  in  dogs'  blood  saturated  with 
air  in  which  the  oxygen  pressure  was  varied.  His  results  indicated 
that  in  presence  of  oxygen  reduced  to  a  pressure  of  about  20  mm. 
the  blood  at  body  temperature  had  lost  half  its  oxygen.  In  a  living 
animal  breathing  air  with  an  oxygen  pressure  of  about  55  mm.  (the 
alveolar  oxygen  pressure  being  unknown)  the  blood  had  also  lost 
half  its  oxygen.  When  the  blood  was  at  a  temperature  below  that 
of  the  body  the  oxygen  was  dissociated  much  less  readily. 

The  subject  was  taken  up  again  by  Hiifner,  who  used  a  solution 
of  oxyhaemoglobin  crystals  in  dilute  sodium  carbonate  solution. 
As  the  result,  partly  of  experiments,  and  partly  of  calculation,  he 
published  in  1890  a  very  symmetrical  curve,  according  to  which 
oxyhaemoglobin  does  not  lose  half  its  oxygen  till  the  oxygen  pres- 

18  Paul  Bert,  La  Pression  Barometrique,  p.  694,  1878. 


RESPIRATION 


69 


sure  is  reduced  to  2.6  mm.14  This  curve  was  totally  at  variance 
with  Paul  Bert's  results,  and  made  it  very  difficult  to  understand 
the  effects  on  animals  breathing  air  with  a  low  oxygen  pressure. 
In  1904  Loewy  and  Zuntz15  published  further  experiments  with 
defibrinated  blood  giving  results  much  nearer  to  those  of  Paul 
Bert.  Meanwhile  the  subject  was  taken  up  by  Bohr,16  who  not  only 
confirmed  Paul  Bert  in  the  main,  but  for  the  first  time  showed  that 
the  dissociation  curve  for  blood  or  haemoglobin  solutions  has  a 
very  peculiar  shape,  with  a  double  bend  (Figure  19) ,  and  that  the 
100 


10   20  30  40  50  60  70  80  90  100  HO  120  130  44O  150 


Figure  19. 

Curves  representing  the  percentage  saturation  of  haemoglobin 
with  oxygen  at  different  partial  pressures  of  oxygen  and  CO2. 
Dog's  blood  at  38°C.  Ordinates  =  percentage  saturation  with 
oxygen ;  abscissae  =  partial  pressures  of  oxygen  in  millimeters 
of  mercury.  (Bohr,  Hasselbalch,  and  Krogh.) 

curve  for  a  haemoglobin  solution  differs  considerably  from  that 
for  blood.  For  this  reason  he  inferred  that  the  haemoglobin  in 
blood  ("haemochrome")  differs  chemically  from  crystallized 
haemoglobin.  Bohr,  Hasselbalch  and  Krogh17  then  made  the 
important  discovery  that  the  dissociation  curve  of  haemoglobin  or 
"haemochrome"  is  greatly  influenced  by  the  partial  pressure  of 
the  CO2  present  (Figure  19),  the  CO2  helping  to  expel  oxygen 
from  its  combination,  so  that,  as  the  blood  takes  up  CO2  in  its 
passage  through  the  capillaries,  oxygen  is  liberated  from  the  oxy- 
haemoglobin  more  readily  than  would  otherwise  be  the  case. 

"Hiifner,  Arch.  f.  (Anat.  u.)  Physwl.,  p.  i,  1890. 

"Loewy  and  Zuntz,  Arch.  f.  (Anat.  u.)  Physwl.,  p.   166,   1904. 

"Bohr,  Centralbl.  f.  Physwl.,  17,  p.  688,  1904. 

17  Skand.  Arch.  f.  Physwl.,  16,  p.  602,  1904. 


70  RESPIRATION 

The  investigation  was  now  taken  up  by  Barcroft  and  his  pupils, 
who  have  made  a  number  of  important  advances  during  the  last 
few  years  with  the  help  of  one  form  or  another  of  the  ferricyanide 
apparatus.18 

They  found  that  the  form  taken  by  the  dissociation  curve  of 
oxyhaemoglobin  is  greatly  influenced  by  the  salts  present  in  the 
red  blood  corpuscles,  or  in  a  solution  of  their  oxyhaemoglobin.19 
When  all  the  salts  were  removed  by  dialysis  the  curve  became  a 
rectangular  hyperbola,20  as  in  the  curve  published  by  Htifner.  If 
the  reversible  reaction  between  oxygen  and  haemoglobin  is  rep- 
resented by  the  uncomplicated  equation  Hb  +  O2*^HbO2,  the 
curve  would,  in  accordance  with  the  well-known  law  of  Guldberg 
and  Waage,  be  a  rectangular  hyperbola.  This  is  the  case  when 
salts  are  absent  and  the  solution  is  neutral,  as  in  the  dialysed  solu- 
tion. When,  however,  salts  are  present,  the  form  of  the  curve  is 
altered  towards  the  characteristic  form  given  by  blood,  and  the 
nature  and  extent  of  the  alteration  was  found  to  depend  on  the 
nature  and  concentration  of  the  salts.  Thus  when  dialysed  dogs' 
haemoglobin  was  dissolved  in  a  salt  solution  of  the  same  composi- 
tion and  concentration  as  in  human  blood  corpuscles  the  dissocia- 
tion curve  obtained  was  similar  to  that  of  human  blood. 

These  discoveries  rendered  it  unnecessary  to  assume  with  Bohr 
and  others  that  there  is  any  essential  chemical  difference  between 
the  haemoglobin  present  in  blood  corpuscles  and  in  a  solution  of 
crystallized  haemoglobin.  At  the  same  time  they  furnished  a  key 
to  the  explanation  of  the  apparently  divergent  observations  as  to 
the  dissociation  curve  of  oxyhaemoglobin.  Barcroft  and  Orbeli21 
found  that  not  only  does  CO2  shift  the  curve  in  the  direction  dis- 
covered by  Bohr  and  his  pupils,  but  that  other  acids  added  in 
such  small  quantities  as  not  to  decompose  the  haemoglobin  have  a 
similar  effect,  while  alkalies  have  the  opposite  effect.  As  will  be 
explained  later  Barcroft  and  his  associates  concluded  that  this 
alteration  affords  a  very  sensitive  measure  of  any  alteration  in  the 
reaction,  or  hydrogen  ion  concentration  of  the  blood;  and  they 
have  used  it  for  this  purpose. 

The  form  of  the  dissociation  curve  of  the  oxyhaemoglobin  in 
human  blood  at  body  temperature  and  with  a  constant  pressure  of 

18  A  summary  of  these  investigations  is  given  in  Barcroft's  book,  The  Respira- 
tory Function  of  the  Blood,  1914. 

19  Barcroft  and  Camis,  Journ.  of  Physiol.,  XXXIX,  p.  118,  1909. 

20  Barcroft  and  Roberts,  Ibid,.,  XXXIX,  p.  143,  1909. 

21  Barcroft  and  Orbeli,  Journ.  of  Physiol.,  XLI,  p.  353,   1910.  Barcroft,  Ibid., 
XLII,  p.  44,  191 1. 


RESPIRATION 


40  mm.  of  CO2,  as  in  average  human  alveolar  air,  was  worked  out 
by  Barcroft,  and  his  results  for  one  individual  (Douglas)  were 


MOO 


18         19        20        21         22        23        24        25        26        27        28        23 
_O_ 


*80 


I  2  34567  8          9          IO         II          12         13        14         13         16         17 

PRESSURE  OF  OXYGEN  IN  PERCENTAGE  OF  ONE  ATMOSPHERE  . 

Figure  20. 

Dissociation  curves  of  oxyhaemoglobin  in  presence  of  40  mm.  pressure  of 
CO2  at  38°  (i  per  cent  of  an  atmosphere  =7.60  mm.  pressure). 

O  Blood  of  C.  G.  D.,  using  ammonia  in  blood-gas  apparatus. 

•  Blood  of  C.  G.  D.,  using  NaaCOs  in  blood-gas  apparatus. 
D   Blood  of  J.  S.  H.,  using  ammonia  in  blood-gas  apparatus. 

•  Blood  of  J.  S.  H.,  using  Na2CO3  in  blood-gas  apparatus. 

X   Mixed  blood  of  six  mice,  using  ammonia  in  blood-gas  apparatus. 

approximately  confirmed  by  Douglas  and  myself,  working  with 
a  different  apparatus.  Figure  20  shows  the  curves  given  by  the 
blood  of  Douglas  and  myself  in  a  very  exact  series  of  observa- 
tions, with  the  individual  observations  marked.  Our  curves  as  will 
be  seen  are  sensibly  the  same;  but  Barcroft  has  found  that  the 
curves  of  different  individuals  may  vary  very  distinctly.  With  the 
blood  of  Douglas  and  myself,  for  instance,  half-saturation  of 
the  haemoglobin  with  oxygen  occurs  at  an  oxygen  pressure  of  4.0 
per  cent  of  an  atmosphere  or  30.4  mm.  With  that  of  other  individ- 
uals, and  the  same  pressure  (40  mm.)  of  CO2,  half -saturation 
may,  according  to  Barcroft,  occur  at  as  low  an  oxygen  pressure  as 
24  mm. 


22 


23  Barcroft,  The  Respiratory  Function  of  the  Blood,  p.  218,   1913. 


72  RESPIRATION 

On  examining  the  dissociation  curve  it  will  be  seen  that  the 
steepest  part  of  the  curve  is  in  the  middle.  In  the  case  of  oxy- 
haemoglobin  dissociating  in  the  living  body  as  the  blood  passes 
through  the  capillaries,  and  in  doing  so  taking  up  CO2,  this  part 
of  the  curve  is  still  steeper,  for  the  reason  given  by  Bohr  and  his 
pupils.  It  is  clear  that  with  this  form  of  curve  the  oxygen  pressure 
in  the  capillaries  must  tend,  after  the  first  fifth  of  the  oxygen  has 
been  given  off,  to  remain  comparatively  steady  during  the  giving 
off  of  the  next  three-fifths :  for  at  this  stage  a  large  amount  of 
oxygen  is  given  off  from  the  oxyhaemoglobin  with  a  compara- 
tively small  fall  in  the  oxygen  pressure.  In  this  way  the  oxygen 
supply  to  the  tissues  is  maintained  at  a  far  higher  and  also  much 
steadier  pressure  than  if  the  curve  were  a  rectangular  hyperbola. 
As  will  be  seen  later,  a  man  would  die  on  the  spot  of  asphyxia  if 
the  oxygen  dissociation  curve  of  his  blood  were  suddenly  altered 
so  as  to  assume  the  form  which  Hiifner  supposed  it  to  have  in  the 
living  body.  The  salts  of  the  red  corpuscles  and  the  particular 
hydrogen  ion  concentration  of  the  blood  are  of  essential  impor- 
tance in  connection  with  the  oxygen  supply  of  the  tissues. 

Haemoglobin,  as  already  mentioned,  forms  specially  colored 
dissociable  compounds,  not  only  with  oxygen,  but  also  with  carbon 
monoxide  and  nitric  oxide,  and  the  compound  with  CO  is  of 
special  physiological  interest,  apart  from  its  practical  importance 
in  connection  with  the  frequency  of  CO  poisoning.  As  compared 
with  the  oxygen  compound  the  CO  compound,  which  was  dis- 
covered by  Claude  Bernard,23  is  characterized  by  its  relative 
stability,  which  is  so  great  that  at  one  time  it  was  supposed  that 
CO-haemoglobin  is  not  dissociable. 

Blood  of  which  the  haemoglobin  is  saturated  with  CO  has  a 
scarlet  color  similar  to  that  of  blood  saturated  with  oxygen ;  but  if 
the  CO-haemoglobin  is  highly  diluted,  or  examined  in  a  very  thin 
layer,  its  color  is  pink,  as  compared  with  the  yellow  color  of  diluted 
oxyhaemoglobin.  By  taking  advantage  of  this  fact  one  can  easily 
recognize  the  presence  of  CO-haemoglobin  in  blood.  This  test,  as 
I  have  often  pointed  out,  is  far  more  delicate  than  the  older 
spectroscopic  test,  but  requires  daylight  or  some  similar  light.  By 
adding  carmine  solution  to  diluted  normal  blood  one  can  exactly 
match  the  color  of  the  diluted  blood  containing  CO,24  and  by 
using  a  suitable  carmine  solution  I  found  it  possible  to  estimate 

33  Claude  Bernard,  Compt.  Rend.,  XLVIII,  p.  393,  1858. 

"A  detailed  description  of  this  method  in  its  latest  form  will  be  found  in 
the  Appendix. 


RESPIRATION 


73 


with  great  accuracy  the  percentage  saturation  of  haemoglobin 
with  CO. 

With  the  help  of  this  method  Douglas  and  I  worked  out  "dis- 
sociation  curves  for  the  CO-haemoglobin  of  human  blood  at 
38 °C — in  the  absence,  of  course,  of  oxygen,  but  in  the  presence 
of  varying  partial  pressure  of  CO2-25  The  results  are  shown  in 
Figure  21. 


too 

90 
80 
70 

50 
40 
30 


10 


4 


c* 


o0</ 


•O05        -010        -015        -O20      -025      -0*30      -035      '040      -O45      -0>5O 

PRESSURE  OF  CO  IN  PERCENTAGE  OF  ONE  ATMOSPHERE. 

Figure  21. 

Dissociation  curves  of  CO  haemoglobin  in  absence  of  oxygen,  at  38°  and 
with  various  pressures  of  CO2.     O  Blood  of  C.  G.  D.     •    Blood  of  J.  S.  H. 

These  curves,  like  the  curve  for  the  oxyhaemoglobin  of  human 
blood  in  Figure  20  are  drawn  free-hand.  On  comparing  them  we 
found  that,  allowing  for  possible  small  errors  due  to  insufficient 
determinations,  they  are  all  the  same  curve  when  the  scale  on 
which  the  abscissae  of  each  are  plotted  is  altered  by  a  suitable 

26  Douglas,  J.  S.  Haldane,  and  J.  B.  S.  Haldane,  Sourn.  of  Physiol.,  XLIV,  p. 
275,  1912. 


74  RESPIRATION 

constant.  It  thus  appears  that  the  effect  of  substituting  CO  for  O2, 
or  of  varying  the  partial  pressure  of  CO2,  is  only  to  alter  a  simple 
constant  in  the  equation  to  the  curve.  In  other  words  it  is  only 
the  affinity  of  haemoglobin  for  the  gas  saturating  it  which  alters. 
With  respect  to  the  oxyhaemoglobin  curve  the  same  conclusion 
was  reached  by  Barcroft  and  Poulton,26  who  found  that  variations 
in  the  partial  pressure  of  CO2  had,  within  wide  limits,  the  same 
effects  on  the  dissociation  curve  of  oxyhaemoglobin,  as  on  that  of 
CO-haemoglobin.  In  the  case  of  Bancroft's  blood  it  requires  a 
little  over  twice  as  high  a  partial  pressure  of  oxygen  to  produce 
half-saturation  of  the  haemoglobin  in  presence  of  40  mm.  pres- 
sure of  CO2  as  when  CO2  is  absent;  just  as  in  the  blood  of  Douglas 
it  takes  a  little  over  twice  as  high  a  partial  pressure  of  CO.  Bar- 
croft  and  Means27  have,  however,  also  shown  that  in  the  case  of  a 
salt-free  or  nearly  salt-free  solution  of  haemoglobin  the  effect  of 
CO2  is  not  merely  to  alter  the  affinity  of  oxygen  for  haemoglobin, 
but  also  to  alter  the  mathematical  form  of  the  curve,  just  as  salts 
do.  Hence  it  is  only  in  the  case  of  whole  blood  that  the  affinity 
alone  is  altered ;  and  probably  we  should  find  that  it  is  only  within 
definite  limits  of  variations  in  the  hydrogen  ion  concentration  of 
whole  blood  that  the  mathematical  form  of  the  dissociation  curve 
is  sensibly  unaltered. 

When  blood  or  haemoglobin  solution  is  exposed  to  a  mixture 
of  CO  and  air  the  haemoglobin  becomes  partly  saturated  with  CO 
and  for  the  rest  with  O2.  I  found  many  years  ago  that  with  a  dilute 
solution  of  blood  the  curve  representing  the  percentage  saturation 
of  the  haemoglobin  with  CO  when  increasing  percentages  of  CO 
are  added  to  the  air  in  the  saturating  vessel  is  a  rectangular  hyper- 
bola.28 Figure  22  shows  curves  obtained  by  Douglas  and  myself 
with  undiluted  blood  at  body  temperature  from  two  persons  and 
two  mice.29 

It  will  be  seen  that  in  each  case  the  curve  is  a  rectangular 
hyperbola,  corresponding  to  the  simple  reversible  reaction  HbO2 
+  CO^HbCO  +  O2.  Thus  for  my  own  blood  the  proportions  of 
HbCO  to  HbO2  are  I  :  I  with  .07  per  cent  of  CO,  2  : 1  with  2  x  .07 
per  cent  of  CO,  3  : 1  with  3  x  .07  per  cent  of  CO,  etc.  For  each  kind 

*"  Barcroft  and  Poulton,  Journ.  of  Physwl.,  XLVI,  Proc.  Physwl.  Soc.,  p.  iv, 
1913- 

87  Barcroft  and  Means,  Journ.  of  Physwl.,  XLVII,  Proc.  Physwl.  Soc.,  p. 
xxvii,  1914. 

"Haldane,  Journ.  of  Physiol.,  Vol.  XVIII,  p.  449,   1895. 

28  Journ.  of  Physiol.,  Vol.  XLIV,  p.  278,  1912. 


RESPIRATION 


75 


of  blood  the  curve  remains  exactly  the  same  when  the  blood  is 
diluted,  or  rendered  less  or  more  alkaline,  or  when  neutral  salts 
are  added.  This  is  of  course  quite  different  from  what  happens 
with  the  simple  dissociation  curves  of  oxyhaemoglobin  and  CO- 
haemoglobin. 


•15        -20       -25 

PERCENTAGE  OFCO. 

Figure  22. 

Dissociation  curves  of  CO  haemoglobin  in  presence  of  air  (20.9  per  cent 
O2)  at  temperature  of  38°.  I.  Blood  of  J.  S.  H.  II.  Blood  of  C.  G.  D.  III. 
Blood  of  mouse  A.  IV.  Blood  of  mouse  B.  The  crosses  indicate  points  deter- 
mined in  the  presence  of  40  mm.  pressure  of  added  COa. 

When  the  percentage  of  CO  in  the  air  is  kept  constant  and  the 
percentage  of  oxygen  is  varied  the  curve  is  again  a  complete  rec- 
tangular hyperbola,  as  shown  in  Figure  23,  provided  that  the  per- 
centage of  CO  is  sufficient  to  saturate  the  haemoglobin  completely 
in  the  absence  of  O2,  as  in  the  upper  curve. 


76 


RESPIRATION 


It  is  thus  evident  that  when  we  have  determined  the  percentage 
saturations  of  a  sample  of  haemoglobin  with  CO  and  O2  in  a  solu- 
tion saturated  with  a  gas  mixture  containing  CO  and  O2  at  known 
concentrations  or  partial  pressures,  what  we  have  really  de- 
termined is  the  relative  affinities  of  the  haemoglobin  for  CO  and 
100 


90 


580 


60 


Q-    10 


\ 


in 


10 


20 


30         40        ,50        60         70 
PERCENTAGE    OF  OXYGEN. 


80         90 


100 


Figure  23. 

Dissociation  curves  of  CO-haemoglobin  in  presence  of  constant  percentage 
of  CO  and  varying  percentage  of  oxygen,  at  atmospheric  pressure.  I.  Blood  of 
J.  S.  H. :  CO  =  0.0945  per  cent.  Blood  of  mouse  C :  CO  =  0.090  per  cent. 
III.  Blood  of  mouse  D  :  CO  =  0.0635  per  cent. 

O2  (without  allowing,  however,  for  the  slight  difference  in  solu- 
bility between  the  two  gases).  In  my  own  blood  the  haemoglobin 
is  equally  divided  between  CO  and  O2  when  the  partial  pressures 
of  CO  and  O2  are  as  .07  to  20.9 — i.e.,  as  I  to  299.  Hence  the 
affinity  of  the  haemoglobin  for  CO  is  299  times  its  affinity  for  O2. 
For  the  haemoglobin  of  Douglas  the  corresponding  figure  is  246. 
For  his  haemoglobin  we  can  also  compare  the  affinities  for  CO  and 


RESPIRATION  77 

O2  in  another  way.  In  presence  of  40  mm.  of  CO2  his  blood  be- 
comes half -saturated  with  CO  (in  the  absence  of  oxygen)  at  a 
pressure  of  .017  per  cent  of  an  atmosphere  of  CO,  as  shown  in 
Figure  21,  and  half -saturated  with  O2  (in  the  absence  of  CO)  at 
a  pressure  of  4.0  per  cent  of  an  atmosphere,  as  shown  in  Figure 
20.  These  pressures  are  in  the  ratio  of  I  1235,  which  is  nearly  the 
same  ratio  as  when  the  relative  affinities  are  estimated  by  the  pre- 
vious method. 

As  already  seen,  we  may  be  able  to  account  for  varying  dis- 
sociation curves  of  the  oxyhaemoglobin  in  whole  blood  by  the 
varying  composition  and  concentration  of  the  salts  contained  in 
the  red  corpuscles,  and  by  varying  alkalinity;  but  we  cannot  so 
account  for  the  varying  relative  affinities  of  different  specimens 
of  haemoglobin  for  CO  and  O2,  since  the  curves  in  Figure  22  are 
not  affected  by  varying  concentration  of  salts  or  degrees  of  alka- 
linity. There  seems  to  be  no  escape  from  the  conclusion  that  in 
different  individuals  of  the  same  species,  as  well  as  in  different 
species,  the  haemoglobin  molecules  are  different.  Whether  the 
haemoglobin  in  each  individual  is  made  up  of  homogeneous  mole- 
cules, or  is  a  mixture  in  some  definite  proportion  of  two  or  more 
different  kinds  of  haemoglobin,  we  do  not  as  yet  know.  What 
seems  pretty  certain,  however,  is  that  each  individual  has  a  specific 
kind  of  haemoglobin  just  as  he  has  a  specific  shape  of  nose.  At 
whatever  time  we  have  investigated  my  own  and  Dr.  Douglas's 
haemoglobin  their  specific  differential  characters  have  appeared 
to  be  sensibly  the  same.  It  seems  pretty  certain  that,  since  the  ratio 
of  oxygen  capacity  to  both  the  coloring  power  and  amount  of 
iron  in  haemoglobin  is  constant,  the  difference  in  the  haemoglobin 
molecule  in  different  kinds  of  blood  is  due  to  the  protein  and  not 
the  haemochromogen  fraction  of  the  molecule;  but  as  yet  there 
are  no  data  to  indicate  more  specifically  the  nature  of  the  differ- 
ence. It  is  of  considerable  biological  significance  to  have  found, 
however,  that,  looking  at  living  organisms  from  a  purely  chemical 
standpoint,  individual  differences  express  themselves,  not  merely 
in  the  relative  amounts  of  the  different  molecules  which  can  be 
separated  from  different  parts  of  the  body,  but  also  in  their  chemi- 
cal constitution. 

Since  the  dissociation  curve  of  CO-haemoglobin  in  presence  of 
a  constant  pressure  of  oxygen  and  varying  pressure  of  CO,  or  in 
presence  of  a  constant  pressure  of  CO  and  varying  pressure  of 
oxygen,  is  a  rectangular  hyperbola,  provided  that  the  gases  are 
present  at  sufficient  pressure  to  saturate  the  haemoglobin,  it  is 


78  RESPIRATION 

clear  that  provided  we  know  the  relative  affinities  of  the  two  gases 
for  the  haemoglobin,  and  the  pressure  at  which  one  is  present,  we 
can  tell  from  an  observation  of  the  percentage  saturation  of  the 
haemoglobin  the  pressure  of  the  other.  Hence  we  can  use  haemo- 
globin solutions  for  determining  small  percentages  of  CO  in  air. 
All  that  is  necessary  is  to  introduce  a  little  blood  solution  into  a 
small  bottle  of  the  air,  shake  till  the  solution  takes  up  no  more  CO, 
and  then  determine  colorimetrically  the  percentage  saturation  of 
the  haemoglobin  with  CO,  and  calculate  the  percentage  of  CO 
present.30  Still  more  important  in  physiological  work  is  the  con- 
verse determination  of  the  oxygen  pressure  by  observation  of  the 
percentage  saturation  of  haemoglobin  exposed  to  a  constant  pres- 
sure of  CO.  By  this  means,  as  we  shall  see  later,  it  is  possible  to 
measure  the  partial  pressure  of  oxygen  in  the  arterial  blood  within 
the  living  body  and  so  decide  the  question  whether  active  secretion 
of  oxygen  inwards  occurs  in  the  lungs. 

Douglas  and  I  found  that  when  the  combined  pressure  of  O2 
and  CO  are  insufficient  to  saturate  the  haemoglobin  the  dissocia- 
tion curve  of  CO-haemoglobin  in  presence  of  a  constant  pressure 
of  CO  and  diminishing  pressure  of  O2  begins  to  diverge  from  the 
rectangular  hyperbola  which  it  would  otherwise  have  followed, 
and  then  proceeds  to  trace  out  the  peculiar  hump  shown  on  the 
lower  two  curves  in  Figure  23,  and  in  greater  detail  in  Figure  24. 
We  thus  have  what  seems  at  first  sight  a  most  anomalous  fact, 
namely  that  although  all  other  facts  show  that  increase  in  the 
pressure  of  oxygen  tends  to  keep  out  CO  more  and  more  from 
combination  with  haemoglobin,  yet  at  very  low  pressure  of  oxygen 
and  CO  the  reverse  is  the  case,  and  increase  of  oxygen  pressure 
helps  the  CO  to  combine  with  haemoglobin.  There  can  be  no  doubt 
that  the  converse  is  also  the  case — namely  that  at  low  pressures  of 
CO  the  presence  of  the  CO  helps  the  oxygen  to  combine  with  the 
haemoglobin.  This  explains  a  very  anomalous  fact  noticed  by 
Lorrain  Smith  and  myself  many  years  ago31 — namely  that  the 
presence  of  a  small  percentage  of  CO  helps  animals  to  resist  the 
effect  of  a  very  low  oxygen  pressure,  or  at  any  rate  does  not  make 
them  worse.  We  had  expected  that  a  given  percentage  of  CO 
would  become  more  and  more  poisonous  the  more  the  oxygen 
pressure  was  diminished,  and  this  was  the  case  within  certain 
limits ;  but  we  were  then  quite  at  a  loss  to  understand  why  with 
very  low  oxygen  pressures  the  CO  seemed  to  do  no  harm. 

""Haldane,  Methods  of  Air  Analysis,  p.  119,  19 1 g. 

"Haldane  and  Lorrain  Smith,  Journ.  of  Physiol.,  XXII,  p.  246,  1897- 


RESPIRATION 


79 


The  explanation  of  the  anomalous  hump  in  the  curves  on  Fig- 
ures 23  and  24  is  in  reality  easy  enough  in  view  of  the  peculiar 
double-bended  form  of  the  simple  dissociation  curves  of  oxy- 
haemoglobin  and  CO-haemoglobin  in  whole  blood.  When  CO  is 
present  at  a  pressure  insufficient  to  saturate  the  blood,  and  the 


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PRESSURE  OF  OXYGEN  IN   PERCENTAGE  OF  ONE   ATMOSPHERE. 

Figure  24. 

Dissociation   curves   of   CO-haemoglobin  in   blood   at   38°    and   in  presence   of 
40  mm.  CO2,  with  constant  pressure  of  CO  and  varying  pressures  of  oxygen. 

oxygen  pressure  is  gradually  raised  from  zero,  the  two  gases  to- 
gether will  trace  out  curves  representing  the  total  saturation  of 
the  haemoglobin,  as  shown  in  the  thin  lines  on  Figure  24.  These 
curves  are  calculated  on  the  theory  that  the  proportion  of  oxy- 
haemoglobin  to  CO-haemoglobin  is  exactly  what  is  required  in 
view  of  the  known  relative  affinities  of  oxygen  and  CO  for  the 
haemoglobin  of  the  blood  used.  As,  however,  the  thin  curves  start 
at  the  steep  part  of  the  joint  curve  a  very  small  addition  of  oxygen 


8o  RESPIRATION 

will  produce  such  a  large  effect  that  not  only  will  a  large  amount 
of  oxygen  go  into  combination,  but  also  an  increased  proportion 
of  CO.  The  thick  lines  show  the  curve  for  CO-haemoglobin  as 
calculated  on  this  hypothesis,  and  the  dots  show  the  actual  ob- 
servations. There  is  in  reality  perfect  agreement  with  the  theory 
that  oxygen  and  CO  combine  with  haemoglobin  in  exact  propor- 
tion to  their  relative  affinities  for  haemoglobin  and  their  partial 
pressures,  just  as  in  the  upper  curve  of  Figure  23.  The  great  sig- 
nificance of  this  in  connection  with  the  explanation  of  CO  poison- 
ing will  be  referred  to  later. 

It  remains  to  discuss  the  explanation  of  the  various  dissocia- 
tion curves  to  which  reference  has  been  made.  We  have  seen  above 
that  Barcroft  and  his  pupils  found  that  when  a  solution  of  oxy- 
haemoglobin  is  freed,  or  approximately  freed,  from  salts  it  gives 
a  dissociation  curve  which  is  a  simple  rectangular  hyperbola,  in 
accordance  with  the  simple  reaction 

Hb  +  O2^HbO2. 

A.  V.  Hill  pointed  out  in  1910  that  the  varying  values  obtained 
for  the  osmotic  pressure  of  haemoglobin  solutions  in  presence  of 
salts  indicates  that  the  molecules  are  more  or  less  aggregated  to- 
gether owing  to  the  influence  of  the  salts ;  and  he  showed  that  this 
fact  was  capable  of  explaining  the  deviation  from  a  rectangular 
hyperbola  of  the  dissociation  curve.  Thus  if,  in  consequence  of 
the  aggregation,  the  reaction  were 

Hb2  +  2O2^Hb2O4, 

the  curve  would  no  longer  be  a  rectangular  hyperbola  but  would 
approximate  to  that  given  for  oxyhaemoglobin  in  presence  of  a 
certain  proportion  of  salts.  By  assuming  a  suitable  proportion  of 
aggregation  of  the  haemoglobin  molecules  as  Hb2,  Hb3,  etc.,  we 
can  therefore  construct  equations  which  will  give  the  actual  dis- 
sociation curves.  He  also  gave  a  general  form  of  equation  to  meet 
the  varying  cases.  In  this  equation  there  are  two  constants,  which 
must  be  suitably  chosen. 

The  subject  was  also  taken  up  by  Douglas,  J.  B.  S.  Haldane, 
and  myself.  We  adopted  Hill's  aggregation  theory,  but  in  a  dif- 
ferent form.  It  seemed  to  us  that  the  aggregation  in  protein  solu- 
tions is  a  phenomenon  of  the  same  general  nature  as  precipitation, 
the  precipitate  being,  however,  only  formed  in  very  small  parti- 
cles consisting  of  only  two,  three,  or  at  any  rate  a  few  molecules. 


RESPIRATION  8  1 

On  this  view  the  aggregated  haemoglobin  molecules  have  their 
molecular  affinities  saturated,  and  therefore  go  out  of  the^e^ 
action  between  oxygen  or  CO  and  haemoglobin,  thus  following 
the  general  principle  that  corpora  non  agunt  nisi  soluta.  The  only 
reaction  taking  place  between  the  haemoglobin  and  oxygen  is  thus 
the  first  one  mentioned  above.  To  explain  the  actual  form  of  the 
dissociation  curve  for  blood  or  salt  solutions  we  assumed  that  the 
degree  of  aggregation  depends  on  the  concentration  of  the  haemo- 
globin or  oxyhaemoglobin  in  the  solution,  in  accordance  with  the 
reactions 


Hb 

Hb  +  Hb2<H±Hb3  etc. 
HbO2  +  HbO2^Hb2O4 
HbO2  +  Hb2O4*±Hb3O6  etc. 

Thus  reduced  haemoglobin  and  oxyhaemoglobin  molecules  ag- 
gregate separately;  and  if  we  assume  that  reduced  haemoglobin 
aggregates  more  readily  than  oxyhaemoglobin  we  can  explain  at 
once  the  distortion  of  the  curve  from  the  primary  rectangular 
hyperbola  obtained  by  Barcroft.  For  as  the  oxyhaemoglobin  be- 
comes reduced  the  aggregation  of  the  reduced  haemoglobin  mole- 
cules must  increase  more  rapidly  than  the  aggregation  of  the 
oxyhaemoglobin  diminishes.  Hence  at  what  would,  but  for  the 
aggregation,  be  half-saturation,  there  are  fewer  free  reduced 
haemoglobin  molecules  and  more  free  oxyhaemoglobin  molecules 
than  would  be  the  case  if  the  oxyhaemoglobin  molecules  aggre- 
gated as  readily  as  the  reduced  haemoglobin  molecules.  Hence 
the  actual  saturation  will  be  much  less  than  half,  and  not  just  half, 
as  would  be  the  case  if  the  tendency  to  aggregation  were  the  same 
for  the  two  kinds  of  molecules.  The  actual  dissociation  curve  will 
also  have  the  double  bend  which  is  characteristic  of  it.  We  also 
assumed  that  the  saturated  molecules  of  HbCO  have  just  as  much 
tendency  to  aggregate  with  one  another  and  with  the  saturated 
molecules  of  HbO2  as  have  the  molecules  of  HbO2.  For  this  reason 
the  dissociation  curve  of  HbCO  in  blood  in  presence  of  oxygen 
must  be  a  rectangular  hyperbola,  as  is  actually  the  case,  though  its 
dissociation  curve  in  the  absence  of  oxygen  has  the  same  form  as 
the  dissociation  curve  of  HbO2. 

By  making  certain  assumptions  (for  a  statement  of  which  I 
must  refer  to  our  original  paper)  J.  B.  S.  Haldane  found  that  the 
following  equation  to  the  curve  for  human  blood  in  Figure  20 


82  RESPIRATION 

resulted,  and  fitted  the  experimentally  determined  curve  very 
closely.32 

1.65     (9—85) 

(I-S)    (I+2S) 

where  p  =  pressure  in  percentages   of   one   atmosphere,    and 
5  =  fractional  saturation  of  the  haemoglobin  with  oxy- 
gen. 

Thus  if  5  be  50  per  cent  =  =  y2,  p  will  be  4.0,  as  we  actu- 
ally found  to  be  the  case.  To  express  the  result  in  millimeters  of 
mercury  pressure,  p  must  of  course  be  multiplied  by  7.6,  and  would 
thus  become,  in  the  above  example,  30.4. 

As  explained  above,  the  simple  dissociation  curves  for  oxy- 
haemoglobin  or  CO-haemoglobin  in  normal  human  blood33  are, 
so  far  as  our  present  knowledge  goes,  the  same,  when  allowance 
is  made  for  the  differing  affinities  of  the  two  gases  for  haemo- 
globin. The  above  equation  may  therefore  be  generalized  in  the 
form 

1.65      (9—85) 


pa  = 


(i— S)  (i+25) 


taking  a  as  representing  the  affinity  of  the  gas  for  haemoglobin 
as  compared  with  the  affinity  represented  in  the  curve  on  Figure 
20,  giving  half-saturation  with  a  gas  pressure  of  4.0  per  cent  of  an 
atmosphere.  Thus  for  the  fourth  curve  on  Figure  21  (dissociation 
curve  of  CO-haemoglobin  in  the  blood  of  Douglas,  in  presence  of 
42  mm.  CO2  pressure),  at  half-saturation  pa  =  4.0.  Hence  as  p 
was  .017,  a  was  235,  or  the  affinity  of  the  haemoglobin  for  the  CO 
(determined  without  taking  into  account  the  solubilities  of  CO  and 
O2)  was  235  times  its  affinity  for  oxygen  in  the  standard  curve  of 
Figure  20.  This  is  a  convenient  and  easily  intelligible  method  of 
putting  the  results. 

82  In  working  out  this  equation  it  was  assumed  that  (as  found  by  Barcroft  and 
Roberts  for  dogs'  haemoglobin)  a  dialysed  solution  of  the  haemoglobin  of  Douglas 
and  myself  becomes  half -saturated  with  oxygen  at  38  °C  and  a  pressure  of  1.6  per 
cent  of  an  atmosphere  of  oxygen,  and  that  in  human  blood  saturated  with  oxygen 
2/3  of  the  oxyhaemoglobin  is  aggregated,  and  in  completely  reduced  blood  8/9  of 
the  reduced  haemoglobin.  The  curve  of  the  dialysed  solution  would  give  the 

i-S 

equation  p  = — 

i.  60 

38  For  abnormal  human  blood  the  curves  are  probably  different,  as  will  be 
pointed  out  in  Chapter  VIII. 


RESPIRATION  83 

The  corresponding  equation  worked  out  by  Hill  is 


y_ 

ioo  zz 

where  x  =  oxygen  pressure  in  mm.  of  mercury, 

y  =i  percentage  saturation  of  the  haemoglobin, 
K  =  a  constant  varying  for  different  curves. 

For  the  blood  of  Douglas  (which  was  the  first  to  be  investi- 
gated completely  by  Barcroft,  and  which  was  also  investigated  by 
ourselves)  the  value  of  K  was  .  000196.  34 

Hill's  equation  gives  curves  almost  identical  with  ours,  and  as 
he  had  kindly  communicated  it  to  us  by  letter  we  should  certainly 
have  adopted  it  had  we  seen  how  the  theory  on  which  it  is  based 
could  be  brought  into  definite  relation  with  the  particular  rec- 
tangular hyperbola  given  by  dialysed  haemoglobin,  or  reconciled 
with  the  fact  that  the  dissociation  curve  of  CO  -haemoglobin  in 
presence  of  a  constant  oxygen  pressure  is  a  rectangular  hyperbola. 
Hill  soon  afterwards  offered  a  possible  explanation  as  regards  the 
latter  point.35  It  seems  to  me  that  this  explanation  is  improbable, 
but  so  also,  it  must  be  confessed,  are  certain  assumptions  connected 
with  the  deduction  of  our  own  equation.  At  present  the  data  are 
lacking  for  a  decision  as  to  whether  either  theory  is  correct,  al- 
though both  equations  are  for  all  practical  purposes  satisfactory. 
I  cannot  see,  however,  how  to  escape  the  conclusion  that  there  is 
more  aggregation  among  the  unsaturated  than  among  the  satu- 
rated molecules  of  haemoglobin.  It  is  evident  that  far  more  data 
are  needed  to  enable  us  to  understand  the  dissociation  of  oxy- 
haemoglobin  in  blood. 

With  the  help  of  the  chemical  facts  described  in  the  present 
chapter  we  might  proceed  at  once  to  the  discussion  of  a  number  of 
physiological  and  pathological  problems;  but  such  a  discussion 
would  be  incomplete  and  misleading  in  the  absence  of  the  facts 
relating  to  the  carriage  of  CO2  by  the  blood,  and  this  subject  will 
therefore  be  considered  in  the  next  chapter. 

34  The  value  of  K  as  calculated  from  our  own  results  (Fig.  20)  is,  for  the  blood 
of  both  Douglas  and  myself,  outside  the  normal  limits  given  by  Barcroft  and  rep- 
resented graphically  in  Figure  109,  page  226,  of  his  book  The  Respiratory  Function 
of  the  Blood,  The  cause  of  this  discrepancy  is  not  yet  clear. 

"A.  V.  Hill,  Bio-Chemical  Journal,  VII,  p.  471,  1913. 


CHAPTER  V 
The  Blood  as  a  Carrier  of  Carbon  Dioxide. 

WE  must  now  turn  to  the  consideration  of  the  blood  as  a  carrier  of 
CO2.  Mammalian  arterial  blood  has  usually  been  found  to  contain 
about  40  or  50  volumes  of  CO2  per  100  volumes  of  blood,  while 
venous  blood  from  the  right  side  of  the  heart  contains  several 
volumes  more.  The  following  average  results  obtained  with  the 
mercurial  pump  by  Schoeffer1  illustrate  the  difference  between 
venous  and  arterial  dogs'  blood,  although  much  doubt  must  exist 
as  to  whether  the  circulation  and  respiration  were  at  normal  rest- 
ing values  when  the  samples  were  taken.  Much  more  reliable  data 
will  be  given  for  man  in  Chapter  X. 


OXYGEN  CO2 

Arterial  blood                                       19.2  39.5 

Venous  blood  from  right  heart           11.9  45.3 

Difference             7.3  5.8 


In  man,  as  will  be  shown  below,  normal  arterial  blood  contains 
during  rest  about  53  volumes  per  cent  of  CO2  if  the  blood  is  satu- 
rated with  CO2  at  the  pressure  (about  40  mm.)  existing  in  average 
alveolar  air  of  adult  men.  As  100  volumes  of  blood,  according  to 
Bohr's2  calculation,  take  up  in  simple  solution  about  51  volumes 
of  CO2  in  presence  of  a  pressure  of  one  atmosphere  of  CO2  at  body 

temperature,  they  can  only  take  up— ~-  x  51  =  2.7  volumes  at  the 

760 

normal  alveolar  pressure  of  40  millimeters  or  5.3  per  cent  of  an 
atmosphere.  Hence  only  2.7  volumes  per  cent  of  the  CO2  are  in 
simple  solution,  the  other  50.3  volumes  being  in  chemical  combi- 
nation. As  will  be  shown  below,  the  difference  between  the  partial 
pressures  of  CO2  in  human  arterial  and  venous  blood  during  rest 
is  only  about  6  mm.  or  0.8  per  cent  of  an  atmosphere.  Hence  the 
physically  dissolved  CO2  given  off  in  the  lungs  is  only  0.4  volumes 

1  Schoeffer,  Sitz.  ber.  d.  Wiener  Acad.,  math.  nat.  cl.,  XLI,  p.  589,  1860. 
8  Bohr,  Nagel's  Handbuch  der  Physiol.,  II,  p.  63,  1905. 


RESPIRATION  85 

per  cent,  while  actually  about  4  volumes  per  cent  are  given  off.  It 
is  evident,  therefore,  that  the  giving  off  of  CO2  in  the  lungs  is 
almost  entirely  dependent  on  the  dissociation  of  its  chemical 
combinations  in  the  blood. 

In  what  form  is  CO2  chemically  combined  in  the  blood?  We 
cannot  answer  this  question  in  the  same  comparatively  simple 
and  definite  manner  as  in  the  case  of  the  combination  of  oxygen 
with  blood.  CO2  dissolved  in  water  has  acid  properties,  and  by  the 
addition  of  other  stronger  acids  to  blood  the  dissociable  chemical 
combinations  with  CO2  are  entirely  broken  up  and  CO2  liberated. 
It  is  thus  quite  evidently  as  an  acid  (i.e.,  as  H2CO3)  that  CO2 
enters  into  combination  with  blood.  On  analysis  blood  is  found  to 
contain  an  excess  of  alkali  (for  the  greater  part  soda)  not  com- 
bined with  mineral  acids.  In  other  words  hydrochloric,  phosphoric, 
and  small  amounts  of  sulphuric,  acids  are  present  in  blood,  but 
not  in  sufficient  amounts  to  saturate  the  alkali.  Hence  CO2  is  ap- 
parently free  to  combine  with  the  excess  of  alkali,  forming,  since 
an  excess  of  free  CO2  is  present,  bicarbonates.  As  Zuntz3  pointed 
out,  if  blood  were  nothing  but  a  solution  of  the  well-recognized 
acids  and  bases  present  in  it,  we  could  account  for  the  quantity  of 
CO2  which  it  is  capable  of  combining  with  chemically.  Zuntz  cal- 
culated that  the  excess  of  alkali  present  in  the  blood  is  equivalent 
to  at  least  a  0.2  per  cent  solution  of  soda.  This  could  take  up  as 
bicarbonate  as  much  CO2  as  blood  can  take  up  in  combination. 
Nevertheless  the  properties  of  such  a  solution  in  respect  to  the 
carriage  of  CO2  would  not  approach  to  those  of  blood:  for  the 
soda  would  remain  completely  saturated  as  bicarbonate  when  ex- 
posed to  the  CO2  in  the  alveolar  air,  and  there  would  not  be  any 
appreciable  dissociation,  so  that  the  solution  would  be  no  better 
than  distilled  water  as  a  physiological  carrier  of  CO2.  This  point 
has  been  rendered  specially  clear  by  Bohr,  who  investigated  the 
dissociation  curve  for  CO2  of  a  dilute  sodium  bicarbonate  solution. 

To  reach  an  insight  into  the  actual  behavior  of  blood  as  a  car- 
rier of  CO2  we  have  to  take  into  consideration  another  factor. 
Proteins  have  the  very  peculiar  property  of  being  able  to  act  either 
as  weak  alkalies  towards  acids  or  as  weak  acids  towards  alkalies. 
This  is  shown,  for  instance,  by  the  familiar  fact  that  an  ordinary 
indicator  such  as  litmus  ceases  to  give  a  sharp  end-point  when  a 
protein  is  present,  and  that  not  only  neutral  but  even  slightly  acid 

'Zuntz,  Hermann's  Handbuch  d,er  Physiol.,  IV,  2,  p.  65,  1882.  To  Zuntz's 
admirably  clear  and  thorough  discussion  of  the  subject  I  am  greatly  indebted.  This 
discussion  is  far  ahead  of  most  of  what  has  appeared  in  later  textbooks  and  papers. 


86  RESPIRATION 

protein  solutions  will  combine  with  CO2.  A  considerable  excess 
of  acid  or  alkali  must  be  added  to  a  neutral  protein  solution  before 
a  marked  acid  or  alkaline  reaction  is  reached.  The  protein  acts  as 
a  "weak,"  or  very  slightly  ionized,  acid,  such  as  carbonic  acid,  and 
likewise  acts  as  a  correspondingly  weak  alkali,  since  the  protein 
molecule  possesses  both  acid  and  alkaline  affinities.  It  is  thus,  like 
carbonic  acid,  or  any  other  weak  acid,  or  weak  alkali,  a  buffer 
substance,  which  prevents  any  abrupt  change  from  acid  to  alkaline 
reaction  or  vice  versa.  Not  until  all  the  CO2  combined  in  a  solu- 
tion of  carbonate  has  been  liberated  by  acid  is  there  a  sudden  de- 
velopment of  acid  reaction,  or  so  long  as  any  free  CO2  is  present 
of  strong  alkaline  reaction.  The  CO2  acts  as  a  buffer  substance  on 
the  alkaline  side  only,  whereas  protein  is  capable  of  acting  on 
either  side  of  the  neutral  point.  In  the  living  body,  however,  blood 
is  always  a  little  alkaline,  so  that  the  combination  of  CO2  with 
proteins  does  not  come  into  account. 

We  can  now  see  a  reason  why  blood  should  act  towards  CO2  as 
it  does  in  the  living  body  and  in  the  vacuum  pump.  The  total 
alkali  in  the  blood  is  combined,  partly  with  strong  acids,  such  as 
HC1,  partly  with  carbonic  acid,  and  partly  with  protein  com- 
pounds ;  partly  also,  perhaps,  with  other  substances  capable  of 
acting,  like  the  proteins,  as  very  weak  acids.  In  the  living  body, 
however,  free  carbonic  acid  is  always  present,  and  the  mass  in- 
fluence of  the  free  carbonic  acid  prevents  part  of  the  protein  from 
combining  with  alkali,  while  the  protein  in  a  similar  manner 
keeps  out  the  carbonic  acid.  We  have  thus  a  chemical  system 
which  is  disturbed  at  once  by  any  variation  in  the  concentration 
of  free  carbonic  acid  present,  i.e.,  by  any  variation  in  the  partial 
pressure  at  which  the  blood  is  saturated  with  CO2.  When  the 
pressure  of  CO2  falls,  more  of  the  proteins  are  at  once  enabled  to 
take  the  place  previously  occupied  by  the  carbonic  acid  in  the 
chemical  combinations  which  constitute  the  system ;  and  vice  versa 
with  a  rise  of  CO2  pressure.  In  the  vacuum  pump  the  CO2  pressure 
is  reduced  to  zero,  since,  although  the  total  pressure  in  the  vacuum 
chamber  of  the  pump  is,  owing  to  aqueous  vapor,  always  above 
zero,  the  CO2  is  carried  off  in  the  stream  of  aqueous  vapor  passing 
away.  To  recover  the  whole  of  this  CO2  in  the  same  gaseous  form, 
however,  a  perfect  and  dry  vacuum  in  the  receiving  chambers  of 
the  pump  is  needed.  Since  the  CO2  pressure  is  zero  the  whole  of  the 
CO2in  combination  is  expelled  by  the  mass  influence  of  protein  act- 
ing as  an  acid.  Pfliiger  showed  that  even  when  a  moderate  amount 
of  sodium  carbonate  is  added  to  blood,  the  additional  CO2  in  the 


RESPIRATION  87 

carbonate  is  expelled  in  the  vacuum  pump,  and  can  be  recovered 
in  the  gaseous  form  with  the  help  of  the  perfect  vacuum  of  the 
Pfliiger  blood  pump.4  This  can  now  be  easily  understood  in  terms 
of  the  theory  just  stated.  The  blood  must  be  either  boiled  or 
shaken :  otherwise  the  disengagement  of  CO2  is  excessively  slow. 

When  serum  alone,  and  not  whole  blood,  is  exposed  to  the 
vacuum  of  the  pump,  most  of  the  CO2  can  be  pumped  out,  but  not 
quite  all.  It  is  necessary  to  add  some  acid  in  order  to  obtain  the 
whole  of  the  CO2 — at  any  rate  within  any  reasonable  time.  The 
proteins  of  the  serum  are  not  present  in  sufficient  amount  to  effect 
the  dissociation  of  the  whole  of  the  sodium  carbonate,  but  the  ex- 
pulsion is  easy  when  the  haemoglobin  of  the  corpuscles  is  added. 
Both  haemoglobin  and  serum  proteins  act  towards  sodium  carbon- 
ate as  acids,  and  it  was  shown  by  Sertoli3  that  much  of  the  CO2 
can  be  expelled  in  the  pump  from  sodium  carbonate  solution  if 
serum  proteins  are  first  added. 

Bohr  found  that  haemoglobin  solutions,  even  if  they  are  first 
rendered  slightly  acid,  will  combine  with  considerable  amounts 
of  CO2,  and  he  was  thus  led  to  what  seems  to  me  to  be  the  er- 
roneous conclusion  that  haemoglobin  has  a  specific  power,  apart 
from  its  alternative  acid  or  basic  properties,  of  combining  with 
CO2.  Equally  erroneous,  as  Priestley6  has  recently  shown,  is  a 
similar  conclusion  which  was  put  forward  on  spectroscopic 
grounds. 

We  have  already  seen  what  predominant  physiological  im- 
portance is  attached  to  the  pressure  of  CO2  in  the  arterial  blood, 
and  with  what  exactitude  this  pressure  is  regulated.  We  should 
therefore  expect  to  find  that  the  pressure  of  CO2  in  the  tissues  of 
the  body  generally  is  of  the  same  importance  and  subject  to  simi- 
lar regulation.  To  understand  this  regulation  it  is  of  primary 
importance  that  we  should  know  the  laws  of  dissociation  of  CO2 
from  its  combination  in  blood.  Until  quite  recently  our  knowledge 
on  this  subject  was  very  limited,  although  Bohr7  had  constructed 
a  tentative  dissociation  curve  from  observations  partly  by  Jacquet 
and  partly  by  himself,  on  samples  of  blood  from  the  ox  and  dog. 

The  matter  was  taken  up  a  short  time  ago  by  Christiansen, 
Douglas  and  myself8  with  the  help  of  the  new  method  of  blood- 

4Pfliiger,  Ueber  die  Kohlensdure  des  Blutes,  p.  6,  1864. 

5  Sertoli,  Hoppe-Seyler's  Med.-Chem.  Unters.,  Ill,  p.  356,  1868. 

9  Priestley,  Journ.  of  Physiol.,  LIII,  Proc.  Physiol.  Soc.,  p.  LVIII,  1920. 

7  Bohr,  Nagel's  Handbook  der  Physiol.,  II,  p.  106,   1905. 

8  Christiansen,   Douglas,  and  Haldane,  Journ.   of  Physiol.,   XLVIII,  p.   244 
1914. 


88 


RESPIRATION 


gas  determination  mentioned  in  Chapter  IV.  Warned  by  previous 
failures  of  physiologists  to  recognize  the  exactitude  of  normal 
physiological  regulations,  we  used  defibrinated  human  blood,  of 
which  fresh  samples  could  be  obtained  at  any  time  from  the  same 
individual  under  normal  conditions.  At  the  outset  we  wasted  much 
time,  however,  through  failing  to  realize  that  it  was  necessary  to 
have  the  blood  fresh  for  each  experiment,  as  blood  outside  the 
body  undergoes  slow  changes  which  diminish  its  capacity  for 
carrying  CO2. 

Figure  25  shows  the  results  obtained  with  my  own  blood. 


ABSORBED  by  100  VOLUMES  of  BLOOD 

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10          20          30          40          5O         60          7O         80          90          100         HO         12 

PRESSURE  of  CO2  in    MM.    Hy. 

Figure  25. 

Lower  curve — absorption  of  CO2  by  blood  of  J.  S.  H.  in  presence  of  air  and  C(>2. 
Upper  curve — absorption  of  CC>2  by  blood  of  J.  S.  H.  in  presence  of  hydrogen  and 
C02. 

Attention  may  first  be  directed  to  the  lower  curve,  showing  the 
amounts  of  CO2  taken  up  in  the  presence  of  air  and  varying  pres- 
sures of  CO2.  The  first,  and  by  far  the  most  striking,  point  to  be 
noted  is  that,  although  the  different  determinations  were  made  on 
different  days  covering  a  period  of  about  six  months,  they  all  lie 
on  one  curve.  The  samples  were  taken  at  different  times  of  the  day 


RESPIRATION  89 

during  ordinary  laboratory  work.  In  regulating  the  temperature 
of  the  bath  containing  the  saturator,  analyzing  the  samples  of  air 
from  the  saturator,  observing  the  barometric  pressure,  measuring 
the  sample  of  blood  (of  which  about  I  cc.  was  used  for  each  anal- 
ysis), and  determining  the  CO2  by  means  of  the  blood-gas  ap- 
paratus (we  used  Brodie's  modification  of  the  original  apparatus), 
it  was  impossible  to  avoid  combined  errors  of  I  or  2  per  cent  of 
the  quantities  to  be  measured,  so  that  we  could  not  say  how  exact 
Nature's  regulation  of  the  curve  is.  At  any  rate  it  was  so  exact 
for  my  blood  that  the  most  exact  existing  chemical  methods  did 
not  show  any  deviations  from  the  curve,  any  more  than  they 
could  show  deviations  from  the  oxyhaemoglobin  or  CO-haemo- 
globin  dissociation  curves.  Marked  temporary  deviations  could, 
however,  be  produced  by  severe  muscular  exertion ;  and  probably 
very  distinct  deviations  may  occur  after  meals. 

With  the  blood  of  other  persons  the  results  were  only  slightly 
different.  Thus  the  curves,  so  far  as  ascertained,  for  the  blood  of 
Miss  Christiansen  and  Dr.  Douglas  were  slightly  below,  and 
otherwise  parallel  to  mine  under  normal  conditions.  The  blood  of 
most  persons  seemed  to  take  up  about  50  volumes  of  CO2  per  100 
volumes  of  blood  at  40  millimeters  pressure  of  CO2;  but  under 
abnormal  conditions,  as  will  be  shown  below,  there  are  great 
temporary  variations  from  this  standard,  corresponding  to  the 
great  variations  observed  under  the  unfavorable  conditions  in 
experiments  on  animals. 

More  than  50  years  ago  it  was  suspected  by  Ludwig  that  oxygen 
may  have  some  influence  in  turning  out  CO2  from  the  venous 
blood  which  conies  to  the  lungs.  The  experiments  made  to  ascer- 
tain whether  oxygen  helps  to  turn  out  CO2  from  blood  gave,  how- 
ever, only  a  negative  result,  and  more  recent  work  by  Bohr, 
Hasselbalch,  and  Krogh9  led  to  similar  negative  conclusions.  We 
had  been  making  experiments  to  investigate  the  rise  of  alveolar 
CO2  pressure  when  the  breath  was  held,  or  when  a  small  quantity 
of  air  was  rebreathed.  One  result  of  these  experiments  was  to  show 
that  if  the  alveolar  oxygen  pressure  fell  much  below  normal  the 
percentage  of  CO2  in  the  alveolar  or  rebreathed  air  was  always, 
without  exception,  lower  after  any  definite  interval  of  time,  than 
was  the  case  under  the  same  conditions  but  with  the  alveolar  oxy- 
gen percentage  high.  This  brought  us  back  to  Ludwig's  old  ques- 
tion, which  with  the  new  blood-gas  method  we  could  investigate 

"Bohr,  Hasselbalch,  and  Krogh,  Skand.  Arch.  f.  Physiol.,  XVI,  p.  411,  1904. 


90  RESPIRATION 

far  more  easily  and  exactly  than  when  nothing  but  the  blood 
pump  and  the  old  methods  of  gas  analysis  were  available. 

The  first  pair  of  experiments  showed  us  that  Ludwig's  old 
suspicion  was  correct,  and  that  at  the  same  pressure  of  CO2  blood 
takes  up  considerably  more  CO2  in  the  absence  than  in  the  presence 
of  oxygen.  The  upper  curve  in  Figure  25  is  the  absorption  curve 
for  my  own  blood  in  the  absence  of  oxygen,  and  shows  that  at  the 
physiologically  important  part  of  the  curve  the  blood  takes  up 
from  5  to  6  volumes  per  cent  more  of  CO2  if  oxygen  is  absent.  We 
found  that  the  excess  of  CO2  taken  up  runs  parallel,  not  to  the 
partial  pressure  of  oxygen,  but  to  the  extent  to  which  the  oxy- 
haemoglobin  of  the  blood  is  dissociated.  Saturation  of  the  haemo- 
globin with  CO  had  just  the  same  effect  on  the  curve  as  saturation 
with  oxygen.  The  effect  may  be  due  to  saturated  haemoglobin 
being  a  less  alkaline  substance  than  reduced  haemoglobin,  but  is 
more  probably  dependent  on  the  molecules  of  reduced  haemo- 
globin having  a  much  greater  tendency  to  aggregate  than  those 
of  saturated  haemoglobin.  The  reasons  for  this  assumption  with 
regard  to  aggregation  were  given  at  the  end  of  last  chapter. 
The  aggregated  haemoglobin  molecules  would  presumably  have 
less  mass  influence  in  keeping  out  the  CO2  from  combination  with 
alkali  than  the  unaggregated  molecules. 

Let  us  now  see  what  physiological  deductions  can  be  drawn 
from  the  absorption  curves  in  Figure  25.  Human  blood  contains 
about  1 8  volumes  per  cent  of  oxygen,  and  if  all  this  oxygen  were 
used  up  in  the  tissues  about  15  volumes  of  CO2  would  be  formed. 
But  during  the  using  up  of  the  oxygen  the  absorption  curve  for 
CO2  starting  from  40  mm.  would  pass  from  the  lower  to  the  upper 
curve  of  Figure  25,  following  upwards  the  thick  line  shown  in 
Figure  26. 

Hence  the  CO2  pressure,  instead  of  rising  to  80  mm.,  as  would  be 
the  case  if  the  lower  curve  were  followed,  would  only  rise  to  62 
mm.  Actually,  as  will  be  shown  later,  not  more  than  about  a  fifth 
of  the  oxygen  is  used  up  during  rest,  so  the  pressure  of  CO2  in  the 
mixed  venous  blood  rises  only  about  5  or  6  mm.  This  makes  it 
far  more  easy  to  understand  why  the  pressure  of  CO2  in  the  arte- 
rial blood  should  be  so  exactly  regulated  as  it  is.  If  it  had  been  the 
case  that  the  resting  CO2  pressure  in  the  systemic  capillaries  were 
far  above  the  arterial  CO2  pressure,  the  necessity  for  such  exact 
regulation  of  the  arterial  CO2  pressure  would  have  been  hard  to 
understand. 

While  the  venous  blood  is  being  aerated  in  the  lungs,  the  ab- 


RESPIRATION 


sorption  curve  for  CO2  will  follow  the  thick  line  downwards.  It 
will  be  seen  that,  if  we  assume  the  resting  excess  pressure  of  CO2 
in  the  venous  blood,  the  quantity  of  CO2  given  off  when  the  CO2 
pressure  in  the  lung  capillaries  falls  to  that  of  the  alveolar  air 
will  be  about  55  per  cent  greater  than  if  no  oxygenation  had  oc- 
curred. If,  on  the  other  hand,  we  assume  a  certain  excess  charge 
75 


50 


40 


/A 


80 


90 


30  40  50  60  70 

PRESSURE  of  CO2    in    MM.     Hq. 

Figure  26. 

Upper  curve — absorption  of  CO2  by  blood  of  J.  S.  H.  in  pres- 
ence of  hydrogen  and  CC>2. 

Middle  curve — absorption  of  COz  by  blood  of  J.  S.  H.  in  pres- 
ence of  hydrogen  and  CC>2. 

Lower  curve — absorption  of  CO2  in  blood  of  ox  and  dog  in  pres- 
ence of  air  and  CO2  (Bohr's  data). 

Thick  line  A — B  represents  the  absorption  of  CO2  by  the  blood 
of  J.  S.  H.  within  the  body. 

of  CO2  in  volumes  per  cent  in  the  venous  blood,  the  discharge  of 
CO2  will  ordinarily  be  about  55  per  cent  greater  than  if  no  oxy- 
genation had  occurred. 

We  can  also  see  that  under  abnormal  conditions,  such  as  may 
easily   occur   when   the  breathing   is   suspended   or   reduced   in 


92  RESPIRATION 

amount,  as  after  forced  breathing,  or  during  excessive  artificial 
respiration,  or  other  respiratory  disturbances,  CO2  may  easily  be 
given  off  by  the  lungs  when  there  is  no  excess  of  venous  over 
alveolar  CO2  pressure,  or  even  when  the  venous  CO2  pressure  is 
considerably  lower  than  that  of  the  alveolar  air.  For  when  the 
blood  reaches  the  lungs  the  process  of  oxygenation  so  reduces  the 
capacity  of  the  blood  for  CO2  that  its  CO2  pressure  is  raised 
above  that  of  the  air,  and  diffusion  results.  If  the  respiratory 
quotient  has  fallen  temporarily  to  a  third  or  less  of  its  normal 
value,  the  thick  line  of  Figure  26  will  become  vertical  in  the  living 
body,  or  incline  to  the  left  instead  of  to  the  right.  It  is  merely 
necessary  to  suspend  the  breathing  for  a  very  short  time  in  order 
to  realize  this  condition.  Only  if  air  containing  a  large  excess  of 
CO2  is  breathed,  will  CO2  be  absorbed  backwards,  and  the  thick 
line  pass  downwards  as  well  as  to  the  left. 

Tlje  discovery  that  oxygenation  of  the  haemoglobin  helps  to 
turn  out  CO2  from  blood  gives  us  the  key  to  the  proper  interpreta- 
tion of  the  fact  that,  as  was  found  by  ourselves  in  human  experi- 
ments, and  earlier  by  Werigo,10  and  by  Bohr  and  Halberstadt,11 
more  CO2  is  given  off  into  the  air  of  the  lungs  when  oxygen  is 
present.  Thus  in  Halberstadt's  experiments  it  was  found  that  if 
one  lung  was  ventilated  with  air,  and  the  other  with  hydrogen, 
the  lung  ventilated  with  air  gave  off  nearly  50  per  cent  more  CO2 
than  the  lung  ventilated  with  hydrogen.  This  result  is  precisely 
what  would  be  expected  in  view  of  the  facts  just  described;  but 
as  Bohr  was  misled  by  the  apparent  results  of  his  experiments 
with  blood  outside  the  body,  he  wrongly  attributed  Halberstadt's 
and  Werigo's  results  to  the  supposed  fact  that  in  presence  of  air 
there  is  a  large  formation  of  CO2  in  the  lungs,  owing  to  a  process 
of  oxidation  occurring  there.  As  will  be  shown  later,  hardly  any 
formation  of  CO2  occurs  in  the  lungs. 

In  a  quite  recent  paper  Parsons12  has  investigated  mathemati- 
cally the  form  of  the  absorption  curve  of  blood  for  CO2  on  the 
theory  that  the  blood  is  a  chemical  system  consisting  of  carbonic 
acid  and  what  may  be  regarded  as  one  other  free  acid  (consisting 
of  the  proteins  present)  with  a  fixed  concentration  of  available 
alkali  distributed  between  them.  This  fixed  concentration  he 
estimated  from  blood-ash  analyses  and  in  other  ways,  to  be  about 
4.5  x  io~2N.  He  found  that  the  form  of  the  curve  given  by  calcula- 

10  Werigo,  Pfliiger's  Archiv.,  LI,  p.  321,  1892. 

11  Bohr,  Nagel's  HancLb.  der  Physiol.,  I,  p.  208. 
13  Parsons,  Journ.  of  PAysiol.,  LIII,  p.  42,  1919. 


RESPIRATION 


93 


tion  corresponded  satisfactorily  with  the  curves  which  both  we 
and  he  had  obtained  experimentally  for  human  blood.  This  is 
illustrated  in  Figure  27,  reproduced  from  his  paper.  We  had  not 
attempted  to  calculate  the  form  of  the  curve,  as  several  proteins 
are  involved  in  the  chemical  system;  but  by  the  simplifying  as- 
sumption which  he  made  Parsons  overcame  this  difficulty. 


Pco, 


10       20      30      40      50      60     7O      8O      9O     IOO    110     120mm. 

Figure  27. 

Comparison  between  the  theoretical  curve  and  experimental  results  for 
completely  reduced  blood  of  Haldane. 

In  the  previous  chapter  we  have  seen  that,  other  things  being 
equal,  a  rise  of  CO2  pressure  shifts  the  dissociation  curve  of  oxy- 
haemoglobin  to  the  right  if  the  curve  is  represented  as  in  Figure 
19  or  28.  In  the  living  body  the  pressure  of  CO2  is  constantly 
rising  as  the  blood  becomes  more  and  more  venous  in  its  passage 
through  the  systemic  capillaries.  The  data  embodied  in  Figure  25 
gave  us  the  means  of  calculating  this  rise,  and  it  will  be  seen  that 
it  is  much  less  than  previously  existing  knowledge  would  have 
led  us  to  believe.  Figure  27  shows  the  oxygen  dissociation  curve 
of  my  own  blood  in  the  living  body,  calculated  from  Figure  26,  on 
the  assumption  that  the  shifting  of  the  curve  to  the  right  is  pro- 
portional to  the  increase  of  CO2  pressure  in  the  blood  as  it  passes 
along  the  systemic  capillaries. 

Bohr  believed  that  the  shifting  of  the  dissociation  curve  to  the 
right  by  the  influence  of  increasing  CO2  pressure  in  the  systemic 


94 


RESPIRATION 


capillaries  is  an  important  factor  in  facilitating  the  unloading  of 
oxygen  from  the  blood ;  and  this  line  of  argument  has  been  further 
elaborated  by  Barcroft.  The  actual  shifting  is,  however,  very 
small  under  normal  conditions,  and  of  much  less  physiological 
importance  than  the  effect  of  the  shifting  of  the  CO2  absorption 
curve  in  consequence  of  reduction  of  oxyhaemoglobin. 


100 

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Pressure  of  oxyyen    in    Percentage  of  one  atmosphere. 

Figure  28. 

The  thick  line  shows  the  dissociation  curve  of  oxyhaemoglobin  in  the  blood  of 
J.  S.  H.  and  C.  G.  D.  in  the  presence  of  40  mm.  pressure  of  COa.  The  thin  line 
represents  the  dissociation  curve  of  oxyhaemoglobin  in  the  blood  of  J.  S.  H.  and 
C.  G.  D.  within  the  body. 

We  are  now  in  a  position  to  interpret  much  more  completely 
the  facts  concerning  the  regulation  of  breathing  by  small  varia- 
tions in  the  alveolar  CO2  pressure.  How  very  small  the  mean 
variations  are,  we  have  already  seen.  On  the  other  hand  the 
breathing  is  constantly  being  interrupted  or  interfered  with  in 
one  way  or  another  during  ordinary  occupations,  such  as  speak- 
ing or  singing,  and  the  breath  can  be  held  for  a  few  seconds  with- 
out any  noticeable  air  hunger  being  produced.  During  these 
interferences  the  alveolar  CO2  pressure  must  be  constantly  rising 
and  falling  on  either  side  of  the  normal  limit,  but  the  physiological 
effect  seems  almost  nil,  and  to  popular  imagination  it  seems  as 
if  the  breathing,  instead  of  being  regulated  so  rigorously  as  was 
shown  to  be  the  case  in  the  second  chapter,  is  hardly  regulated  at 


RESPIRATION  95 

all.  We  are  also  familiar  with  instructions  to  increase  the  breathing 
so  as  to  "improve  the  oxygenation  of  the  blood"  and  with  quack 
advertisements  based  on  the  same  idea.  How  does  it  come  about 
that  although  the  regulation  is  so  exact  on  the  average,  yet 
temporary  deviations  from  this  average  exactitude  do  not  cause 
any  discomfort?  How  is  it,  also,  that  when  the  production  of  CO2 
is  suddenly  increased  to  perhaps  ten  times  the  normal,  as  on  a 
sudden  muscular  exertion,  yet  the  breathing  responds  gradually 
and  easily  to  the  new  conditions? 

The  answer  to  this  question  is  that  there  are  physiological  buf- 
fers between  the  stimulus  of  increased  production  of  CO2,  or 
increase  in  the  alveolar  CO2  pressure,  and  stimulation  of  the 
respiratory  center,  and  that  if  it  were  not  so  the  respiratory  center 
would  work  in  a  jerky,  irregular,  and  extremely  inconvenient 
manner.  The  first  of  these  buffers  is  the  large  volume  of  air  always 
present  in  the  lungs.  Thus  in  my  own  case  the  mean  volume  of  air 
in  the  lungs  at  the  end  of  inspiration  during  rest  is  3650  cc., 
measured  dry  at  o°C,  including  about  3000  cc.  of  saccular  al- 
veolar air  containing  about  5.6  per  cent  of  CO2.  Let  us  assume 
that  the  breath  is  held  at  the  end  of  inspiration  during  rest,  and 
consider  what  happens.  About  250  cc.  of  CO2  would  be  normally 
given  off  per  minute,  or  20  cc.  in  5  seconds;  and  if  the  latter 
quantity  were  given  off  with  the  breath  held  the  mean  CO2  pres- 
sure in  the  lung  air  would  rise  by  0.6  per  cent  in  5  seconds.  But, 
as  will  be  shown  later,  about  700  cc.  of  blood  will  pass  through  the 
lungs  in  5  seconds,  and  as  the  arterial  blood  will  be  more  highly 
saturated  with  CO2  if  the  alveolar  CO2  percentage  rises,  some  of 
the  CO2  which  would  ordinarily  have  been  given  off  will  be 
dammed  back  in  the  blood.  Figure  25  shows  that  for  every  rise  of 
2.5  mm.  or  .36  per  cent  in  the  alveolar  CO2  pressure  the  blood  will 
take  up,  or  hold  back,  i  volume  per  cent  of  CO2.  Hence  the  actual 
rise  in  the  mean  CO2  pressure  within  the  lungs  cannot  be  more 
than  about  0.4  per  cent  in  the  5  seconds  during  which  the  breath 
is  held.  The  net  result  is  that  about  two-thirds  of  the  CO2  which 
the  suspension  of  the  breathing  prevents  from  escaping  from  the 
body  is  temporarily  accommodated  in  the  lung  air,  which  thus 
acts  as  a  first  buffer  for  preventing  too  sudden  a  change  in  the 
arterial  CO2  pressure. 

A  second  buffer  is  provided  by  the  tissues  and  lymph  in  and 
around  the  respiratory  center  itself.  So  far  as  we  know  the  re- 
action in  all  parts  of  the  body  is  slightly  alkaline,  just  as  in  the 
blood;  and  the  tissues  and  lymph  have,  like  the  blood,  a  con- 


96 


RESPIRATION 


siderable  capacity  for  absorbing  CO2.  Hence  it  will  take  some 
time  for  the  blood  to  saturate  the  tissues  and  lymph  up,  or  de- 
saturate  them  down,  to  a  new  CO2  pressure.  Here  we  have  a 
second,  and  very  powerful,  buffer  action,  tending  to  smooth  out 
the  influence  on  the  respiratory  center  and  other  tissues  of  all 
variations  of  short  duration  in  the  CO2  pressure  of  the  arterial 
blood,  and  also  to  prolong  the  influence  of  variations  of  longer 
duration. 

This  subject  was  investigated  by  Douglas  and  myself.13  The 
following  table  shows  the  results  we  obtained  on  determining  the 
alveolar  CO2  pressure  at  various  times  after  holding  the  breath. 
In  order  to  throw  out  disturbing  effects  due  to  the  action  of  oxy- 
gen want  on  the  respiratory  center,  some  of  the  experiments  were 
made  after  a  few  normal  breaths  of  oxygen  had  been  taken,  so  that 
there  should  be  plenty  of  oxygen  in  the  lungs  up  to  the  end  of  the 
stoppage  of  respiration. 


PRESSURE  IN 

MM.  OF 

HG.  IN  ALVEOLAR  AIR 

C02 

02 

At  end  of  period  of  holding  breath  for  30" 

49.2 

62.6 

At  fifth  expiration  following 

29.1 

— 

At  ninth  expiration  following 

31-5 

— 

At  twelfth  expiration  following 

32.0 

— 

At  twentieth  expiration  following 

33-8 

— 

At  thirtieth  expiration  following 

37-0 

— 

At  fortieth  expiration  following 

38.8 

— 

At  fifth  expiration  after  holding  40" 

28.4 

117. 

At  eighth  expiration  following 

29.4 

At  end  of  holding  breath  for  130"  after  oxygen 

61.9 

274. 

At  sixth  expiration  afterwards 

24.8 

At  twentieth  expiration  afterwards 

33-3 

— 

At  fortieth  expiration  afterwards 

31-2 

— 

Normal  average 

39-75 

105. 

Figure  29  is  a  stethographic  tracing  of  the  respirations  during 
an  experiment,  and  shows  that  the  breathing  returns  gradually 
to  normal  after  the  hyperpnoea  following  the  stoppage. 

The  table  is  extremely  instructive,  and  shows  very  clearly  what 
a  long  period  of  increased  breathing,  with  the  alveolar  CO2  pres- 
sure distinctly  below  normal,  is  required  in  order  to  compensate 

13  Douglas  and  Haldane,  Journ.  of  Physwl.,  XXXVIII,  p.  420,  1919. 


I 


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98  RESPIRATION 

for  the  cumulative  action  of  the  stoppage  of  breathing.  After  the 
long  stoppage  of  130  seconds  the  breathing  and  alveolar  CO2 
pressure  had  not  nearly  returned  to  normal,  even  after  the  fortieth 
breath  following  the  stoppage. 

Figure  30  shows  the  converse  experiment.  Forced  breathing 
was  continued  two  minutes  so  as  to  wash  out  CO2  from  the  lungs, 
arterial  blood,  and  respiratory  center;  and  oxygen  had  been  taken 
into  the  lungs,  so  as  to  cut  out  the  effects  of  want  of  oxygen.  The 
apnoea  lasted  4%  minutes,  and  an  alveolar  sample  (the  taking  of 
which  is  recorded  on  the  tracing  and  somewhat  disturbs  it)  was 
obtained  as  soon  as  the  slightest  inclination  to  breathe  was  noticed. 
It  will  be  seen  that  the  CO2  percentage  in  this  sample  was  7.12 
per  cent  (51.5  mm.  of  CO2  pressure)  a  value  far  above  the  normal 
40  mm.  required  to  excite  the  center  under  normal  conditions. 
Separate  experiments  showed  that  by  the  end  of  two  minutes  of 
forced  breathing  the  alveolar  CO2  pressure  had  fallen  to  about 
13  mm.  and  during  the  apnoea  rose  to  normal  again  at  the  end  of 
2j^  minutes.  During  the  last  2  minutes  the  alveolar  CO2  pressure 
was  above  normal ;  but  sufficient  CO2  had  not  accumulated  in  the 
tissues  of  the  respiratory  center  to  stimulate  it,  till  the  alveolar 
CO2  pressure  had  gradually  risen  to  51.5  mm.  At  this  point  the 
center,  which  had  now  just  reached  its  normal  CO2  pressure,  began 
to  work  quietly  and  smoothly,  reducing  the  alveolar  CO2  pressure 
to  normal,  and  picking  up  the  normal  regulating  activity.  The 
breathing  cannot  indicate  a  gradual  return  of  the  CO2  pressure 
in  the  center  to  normal,  corresponding  to  the  gradual  return  in 
Figure  29,  since,  as  is  shown  by  the  experiments  described  in 
Chapter  II,  complete  apnoea  results  from  a  fall  of  0.2  per  cent  or 
1.5  mm.  of  the  CO2  pressure  in  the  respiratory  center. 

The  apnoea  following  forced  breathing  can  be  temporarily 
interrupted  by  sending  a  block  of  blood  highly  charged  with  CO2 
to  the  respiratory  center.  The  effect  of  this  is  shown  in  Figure  31. 
As  soon  as  the  breathing  and  the  "apnoeic"  venous  blood  return- 
ing to  the  lungs  have  removed  the  extra  CO2  introduced  into  the 
lungs  the  apnoea  returns  again. 

The  washing  out  of  CO2  from  the  body  during  forced  breath- 
ing, and  its  gradual  reaccumulation  during  the  next  ten  or  twenty 
minutes,  were  strikingly  illustrated  in  some  experiments  carried 
out  by  Boothby.14  Thus  in  an  experiment  on  myself  he  found  that 
during  i*/2  minutes  of  forced  breathing  I  had  removed  about 
1,400  cc.  extra  of  CO2  from  the  body.  During  the  subsequent  ap- 

14  Boothby,  Journ.  of  Physwl.,  XLV,  p.  328,  1912. 


RESPIRATION 


99 


noea  of  2  minutes  about  600  cc.  of  CO2  were  regained,  and  about 
200  cc.  more  during  two  minutes  of  periodic  breathing  which 
followed.  The  remainder  was  regained  during  the  following  six 
or  eight  minutes.  In  this  latter  period  the  alveolar  CO2  pressure 


Figure  31. 

Effect  of  a  breath  of  air  containing  9.0  per  cent  of  CO2  during  apnoea  follow- 
ing forced  breathing.  Crosses  show  inspiration  and  expiration  of  breath.  After 
an  interval  there  are  three  deep,  and  two  shallow,  breaths,  followed  by  a  long 
apnoeic  interval,  after  which  the  usual  periodic  breathing  begins.  To  read 
from  left  to  right.  Time-marker  =  i  second. 

was  practically  normal,  but  the  respiratory  quotient  very  low,  in 
correspondence  with  the  very  high  respiratory  quotient  during 
the  forced  breathing. 

What  approximately  happens  to  the  CO2  pressure  in  the  al- 
veolar air  and  respiratory  center  is  represented  in  Figures  32  and 

-so 


-40 


-30 


-10 


Time  in  Minutes 

Figure  32. 

Approximate  variations  in  CO2  pressure  of  arterial  and  venous  blood  dur- 
ing and  after  forced  breathing  of  oxygen  for  two  minutes. 

33.  The  pressure  of  CO2  in  the  respiratory  center  is  assumed  to  be 
about  equal  to  that  of  the  mixed  venous  blood,  though  it  is  prob- 
ably lower. 


100 


RESPIRATION 


The  very  powerful  steadying  influence  on  the  CO2  pressure  of 
the  capacity  of  the  tissues  for  taking  up  CO2  is  evident  from  these 
figures.  In  consequence  of  this  influence,  and  in  a  much  less  degree 
that  of  the  reserve  of  air  in  the  lungs,  variations  of  short  duration 
in  the  alveolar  CO2  pressure  hardly  count,  although  even  the 
slightest  variations  of  a  more  prolonged  character  count  a  great 
deal. 


2  4 

T/ne  in  Minutes 

Figure  33. 

Approximate  variations  in  COa  pressure  of  arterial 
and  venous  blood  during  and  after  holding  the  breath 
for  130  seconds  with  oxygen. 

On  examining  Figure  32  it  will  be  seen  that,  although  the 
venous  CO2  pressure  is  below  that  of  the  alveolar  air  during  most 
of  the  apnoea,  CO2  is  being  given  off  all  the  time  into  the  alveolar 
air.  This  is  due  to  the  effect  of  oxygenation  in  decreasing  the 
capacity  for  CO2  and  thus  raising  its  pressure  in  the  blood.  This 
effect  is  explained  by  the  fact  that  the  thick  line  of  Figure  26  will 
be  inclined  to  the  left,  as  very  little  CO2  is  being  given  off  by  the 
tissues,  impoverished  as  they  are  of  CO2  by  the  forced  breathing. 

In  order  to  realize  how  important  the  steadying  influence  just 
mentioned  is,  we  have  only  to  turn  to  what  happens  when  want 
of  oxygen,  instead  of  CO2,  is  exciting  the  center.  Oxygen  is  no 


fil 

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102 


RESPIRATION 


more  soluble  in  the  tissues  and  lymph  than  in  water.  They  have 
thus  practically  no  power  of  storing  free  oxygen.  In  the  course  of 
our  investigations  on  the  effects  of  want  of  oxygen  it  became 
evident  that  the  center  works  very  jerkily  when  excited  by  want 
of  oxygen,  and  the  subject  was  studied  in  further  detail  by  Doug- 
las and  myself.15  We  found  that  the  effects  of  regulation  of  the 
center  by  oxygen  want  could  be  observed  very  conveniently  at 
the  end  of  the  apnoea  caused  by  forced  breathing  of  ordinary  air. 
When  apnoea  is  produced  by  forced  breathing  of  air  for  about 
two  minutes,  the  oxygen  percentage  in  the  lungs  runs  down  very 
low  before  the  pressure  of  CO2  in  the  respiratory  center  has  nearly 
risen  to  its  normal  value.  In  some  subjects  there  is  an  alarming 


fr-4 


VK.  Mf 


mv.'i\Mi'.',lr, 

Figure  35. 

Variations  in  alveolar  gas  pressures  after  forced  breathing 
for  two  minutes.  Thin  line  =  oxygen  pressure,  thick  line  =  CO2 
pressure.  Double  line  =  normal  alveolar  CO2  pressure.  The 
actual  breathing  is  indicated  at  the  lower  part  of  the  figure. 

appearance  of  blueness  in  the  face  before  any  desire  to  breathe  is 
felt.  Ultimately,  however,  the  stimulus  of  oxygen  want  (together 
with  the  subliminal  CO2  stimulus)  suffices  to  start  the  breathing. 
But  the  first  four  or  five  breaths  greatly  raise  the  alveolar  oxygen 
percentage  and  thus  quiet  the  center  down  again,  so  that  apnoea 
again  follows,  which  is  again  followed  by  breathing  and  subse- 
quent apnoea,  this  periodic  rising  and  dying  away  of  the  breath- 
ing going  on  for  about  five  minutes,  as  shown  in  Figure  34,  though 
not  all  subjects  react  alike. 

Figure  35  shows  the  variations  of  the  alveolar  oxygen  and  CO2 

"Douglas  and  Haldane,  Journ.  of  PAysiol.,  XXXVIII,  p.  401,  1909. 


RESPIRATION  103 

pressure,  as  determined  in  samples  of  alveolar  air.  Reference  to 
Figure  31  shows  that  at  no  time  during  the  periodic  breathing  is 
the  CO2  pressure  in  the  respiratory  center  more  than  just  suf- 
ficient to  excite  the  center  by  itself. 

It  is  very  easy  to  see  what  has  been  happening.  The  oxygen 
want  caused  by  the  partially  reduced  blood  coming  from  the 
lungs  at  the  end  of  the  apnoea  has,  along  with  the  CO2  present, 
sufficed  to  excite  the  center;  but  this  oxygen  want  is  at  once  re- 
lieved by  the  breaths  which  follow,  since  the  oxygen  pressure  in 
the  lungs  is  raised  beyond  the  exciting  point.  The  result  is  a 
prompt  return  of  the  apnoea,  till  the  oxygen  in  the  alveolar  air 
again  returns  to  the  stimulating  point.  The  respiratory  governor 
is  "hunting"  just  as  the  governor  of  a  steam  engine  or  turbine 
hunts  if  there  is  no  heavy  flywheel  or  other  steadying  influence. 
The  chief  flywheel  of  the  respiratory  center  is  the  great  storage 


Figure  36. 

Breathing  through  soda  lime  and  long  tube.  Sample  of  alveolar 
air  at  the  end  of  a  dyspnoeic  period,  Oz=  8.70  per  cent,  CO2=  5.48 
per  cent. 


capacity  in  the  tissues  for  CO2.  There  is  no  such  storage  capacity 
in  connection  with  oxygen,  so  the  flywheel  has  disappeared. 

When  slight  oxygen  want,  and  not  merely  excess  of  CO2,  is 
exciting  the  center,  the  breathing  very  readily  becomes  periodic. 
To  realize  this  condition  in  a  permanent  manner  we  only  had  to 
breathe  in  and  out  through  a  tin  of  soda  lime  with  a  piece  of  hose 
pipe  of  variable  length  attached  on  the  far  side,  so  as  to  give  a 
suitable  dead  space.  By  this  means  the  alveolar  oxygen  pressure 
can  be  reduced  to  any  required  extent.  Figure  36  shows  the  effect 
of  such  an  arrangement.  This  effect  is  at  once  knocked  out  if  oxy- 
gen is  breathed. 


104  RESPIRATION 

Some  years  ago  it  was  discovered  by  Pembrey  and  Allen16  that 
the  well-known  pathological  form  of  periodic  breathing  named 
after  Drs.  Cheyne  and  Stokes,  who  described  it  (though  it  was 
previously  described  by  John  Hunter),  is  abolished  by  giving  the 
patient  pure  oxygen  to  breathe.  This  observation  indicates  with 
great  certainty  that  ordinary  pathological  Cheyne-Stokes  breath- 
ing is  caused  also  by  want  of  oxygen  participating  in  the  excita- 
tion of  the  center.  Pathological  periodic  breathing  and  that  of 
hibernating  animals  will  be  discussed  later. 

The  normal  pressure  of  oxygen  in  the  alveolar  air  is  about 
100  mm.  or  13.1  per  cent  of  an  atmosphere.  On  looking  at  the 
dissociation  curve  of  oxyhaemoglobin  in  human  blood  (Figure 
20)  it  will  be  seen  that  a  fall  of  4  per  cent  of  an  atmosphere,  or 
30  mm.,  makes  very  little  difference  to  the  saturation  of  the  haemo- 
globin. Nor  has  such  a  fall  any  appreciable  influence  on  the  rest- 
ing breathing  at  the  time.  It  is  thus  evident  that,  although  there 
is  no  appreciable  store  of  readily  available  oxygen  in  the  liquids 
of  the  body  outside  the  red  corpuscles  and  certain  muscles  which 
contain  a  little  haemoglobin,  there  is  a  store  of  oxygen,  available 
without  any  inconvenience,  in  the  air  of  the  lungs.  If  the  breathing 
is  temporarily  stopped  during  some  occupation  this  store  is  drawn 
on.  Thus  if  the  breath  is  held  for  half  a  minute  the  oxygen  runs 
down  by  about  4  per  cent  in  the  alveolar  air  during  rest ;  but  under 
normal  conditions  it  is  quite  impossible  to  hold  the  breath  long 
enough  to  imperil  seriously  the  oxygen  supply  to  the  tissues.  In 
spite  of  the  gradual  manner  in  which,  as  we  have  just  seen,  CO2 
acts  on  the  respiratory  center,  there  is  never,  except  under  very 
artificial  conditions,  any  considerable  oxygen  want.  The  com- 
paratively large  volume  of  air  which  is  always  in  the  lungs  gives 
sufficient  oxygen  storage  to  guard  against  the  temporary  want  of 
oxygen.  Were  this  amount  of  air  much  less  the  danger  would  be 
always  present,  and,  as  we  shall  see  later,  this  danger  or  incon- 
venience is  present  at  high  altitudes,  when  the  mass  of  oxygen  in 
the  lungs  is  greatly  diminished.  At  a  high  altitude  one  cannot 
hold  the  breath  for  more  than  a  few  seconds  without  feeling  an 
imperative  desire  to  breathe,  and  such  operations  as  shaving,  or 
reading  a  barometer,  are  thus  rendered  troublesome.  Nature  sees 
to  it  that  ordinary  mortals  who  live  under  a  pressure  of  about  one 
atmosphere  carry  about  sufficient  oxygen  in  their  lungs  to  pre- 
vent oxygen  want;  and  there  seems  to  be  some  evidence  that 

16  Pembrey  and  Allen,  Journ.  of  Physiol.,  XXXII,  Proc.  Physiol.  Soc.,  p.  xviii, 
1905  ;  also  Medico-  Chirurg.  Trans.,  XI,  p.  49,  1907. 


RESPIRATION  105 

persons  who  inhabit  very  high  parts  of  the  earth  develop  a  greatly 
increased  chest  capacity. 

Addendum.  The  account  given  in  this  chapter  of  the  manner  in 
which  CO2  is  carried  by  the  blood  represents  what  I  have  taught 
for  many  years,  and  is  largely  based,  as  mentioned  above,  on  the 
teaching  of  Pfliiger  and  Zuntz.  A  very  different  view  of  the 
subject  has  recently  been  presented  by  Buckmaster,  Bayliss,  and 
others.  According  to  this  view  the  extra  CO2  taken  up  in  the 
venous  blood  is  combined,  not  with  alkali,  but  with  haemoglobin, 
and  may  also  be  in  part  adsorbed  by  haemoglobin  and  other 
proteins.  As  evidence  that  haemoglobin  and  other  proteins  do 
not  play  the  part  of  weak  acids  in  expelling  CO2  from  its  combi- 
nation with  alkali,  Buckmaster  cites  experiments  in  which  he 
found  that,  contrary  to  Pfliiger's  statement,  blood  or  haemo- 
globin is  not  capable  of  expelling  CO2  from  a  weak  carbonate 
solution  in  the  vacuum  of  a  blood  pump  at  body  temperature.1 
It  seems  to  me  that  these  experiments  were  fallacious  because  the 
blood  was  neither  boiled  nor  shaken.  Boiling,  shaking,  or  bubbling 
is  necessary  to  remove  the  CO2.  When  Pfliiger's  experiment  was 
repeated  in  a  simple  form  by  Adolph  in  my  laboratory  the  ex- 
pulsion of  CO2  from  sodium  carbonate  by  blood  was  found  to 
occur  quite  readily.2  As  already  mentioned,  Buckmaster's  con- 
tention that  haemoglobin  gives  a  characteristic  spectrum  with 
CO2  was  also  found  to  be  incorrect. 

The  supposition  that  an  extra  amount  of  gas  is  adsorbed  by  the 
proteins  of  blood  has  no  basis.  The  careful  experiments  of  Bohr 
and  other  previous  observers  show  clearly  that  apart  from  chemi- 
cal combination  blood  takes  up,  not  more,  but  considerably  less, 
gas  than  an  equal  volume  of  water.  The  only  apparent  exception 
to  this  rule  was  the  fact  that  oxygenated  blood  (but  not  reduced 
blood)  yields  slightly  more  nitrogen  than  the  quantity  calculated 
from  its  estimated  solubility.  The  existence  of  this  small  surplus 
was  confirmed  by  Buckmaster  and  Gardner.3  The  apparent  surplus 
is  almost  certainly  due  to  what  is  a  rather  common  source  of 
slight  error  in  gas  analysis.  When  the  gas  pumped  off  from  oxy- 
genated blood  is  analyzed,  the  first  step  is  to  bring  the  gas  into 
contact  with  potash  solution  to  absorb  the  CO2.  When  this  is  ab- 
sorbed a  gas  mixture  consisting  almost  wholly  of  oxygen  is  left 
in  contact  with  the  potash  solution.  But  the  latter  is  saturated 

1  Buckmaster,  Journ.  of  Phystol.,  LI,  p.  105,   1917. 

'Adolph,  Journ.  of  Physiol.,  LIV,  Proc.  Physiol.  Soc.  p.  XXXIV,  1920. 

8  Buckmaster  and  Gardner,  Journ.  of  Physwl.,  XLIII,  p.  401,   1912. 


106  RESPIRATION 

with  air,  and  as  a  consequence  nitrogen  diffuses  from  the  potash 
solution  into  the  gas  mixture,  while  oxygen  diffuses  into  the 
potash  solution.  The  consequence  is  that  the  residue  of  nitrogen 
found  in  the  gas  after  the  oxygen  has  been  absorbed  is  greater 
than  was  originally  present  in  the  gas.  This  source  of  error  is 
absent  if  little  or  no  oxygen  is  present  in  the  gas  pumped  off  from 
the  blood.  We  can  thus  explain  why  no  extra  nitrogen  has  been 
found  in  reduced  blood. 

Bayliss4  contends  that  the  bicarbonate  and  the  plasma  proteins 
present  in  blood  play  no  part  in  the  physiological  carriage  of 
CO2  between  the  tissues  and  the  lungs,  and  that  haemoglobin  is 
alone  concerned  in  the  carriage,  since  it  does  not,  under  actual 
physiological  conditions,  compete  as  an  acid  with  CO2  for  the 
alkali  available  in  the  blood.  The  experiments  cited  in  support  of 
this  conclusion  seem  to  me  quite  unconvincing;  and  if  it  were  cor- 
rect we  should  expect  to  find  that  blood  saturated  at  the  alveolar 
partial  pressure  with  CO2  would  contain  more  combined  CO2  than 
a  solution  of  bicarbonate  of  the  same  strength  in  titratable  alkali 
as  the  blood.  Actually,  the  blood,  especially  at  body  temperature, 
contains  far  less  combined  CO2.  It  seems  quite  impossible  to 
reconcile  Bayliss'  theory  with  this  fact ;  and  I  cannot  see  how  any 
other  theory  than  that  given  in  the  first  part  of  this  chapter  is 
capable  of  interpreting  the  facts  as  a  whole.  It  may  be  that  a  small 
amount  of  CO2  is  combined  with  free  haemoglobin ;  but  it  seems 
evident  that  under  physiological  conditions  haemoglobin  and 
other  proteins  act,  for  all  practical  purposes,  simply  as  weak  acids. 
It  is  in  virtue  of  this  action,  and  the  more  powerful  action  of 
oxyhaemoglobin  than  reduced  haemoglobin  as  an  acid,  that  blood 
functions  so  efficiently  as  a  physiological  carrier  of  CO2.  Campbell 
and  Poulton,  who  entirely  disagree,  and  on  substantially  the  same 
grounds  as  I  do,  with  the  conclusions  of  Buckmaster  and  Bayliss, 
have  recently  shown  that  an  artificial  mixture  of  dialysed  cor- 
puscles and  dilute  sodium  bicarbonate  solution  takes  up,  within 
physiological  limits  of  CO2  pressure,  much  less  CO2  than  the 
bicarbonate  alone  holds.5 

For  the  sake  of  simplicity  I  did  not  discuss  separately  the 
action  of  plasma  and  corpuscles  in  combining  with  CO2 ;  but  much 
attention  has  been  given  recently  to  this  subject.  Zuntz6  pointed 
out  that  when  plasma  or  serum  is  separated  from  blood  collected 

4Bayliss,  Journ.  of  Physiol.,  LIII,  p.   162,   1919. 

5  Campbell  and  Poulton,  Journ.  of  Physiol.,  LIV,  p.  157,  1920. 

6  Zuntz,  Hermann's  H '  andbuch  der  Physiol.,  IV,  2,  p.  77,   1882. 


RESPIRATION  107 

as  it  flows  from  a  vessel,  the  corpuscles  are  capable  of  taking  up 
from  pure  CO2>  more  combined  CO2  than  an  equal  volume  _pf 
the  plasma.  If,  on  the  other  hand,  the  blood  is  artificially  saturated 
with  pure  CO2,  or  air  containing  a  high  percentage  of  CO2,  and 
then  separated  into  plasma  and  corpuscles,  the  plasma  contains 
more  combined  CO2  than  the  corpuscles.  He  concluded  that  alkali 
previously  combined  with  haemoglobin  in  the  corpuscles  combines 
with  CO2  when  a  high  concentration  of  the  latter  is  present,  and 
passes  out  as  bicarbonate  into  the  plasma.  Further  investigation 
of  this  phenomenon  by  Giirber7  showed  that  alkali  does  not  pass 
out  of  the  corpuscles,  but  acid  passes  in,  leaving  the  corresponding 
alkali  behind  in  the  plasma.  The  walls  of  the  corpuscles  seem, 
therefore,  as  Hamburger8  in  particular  has  pointed  out,  to  be 
practically  impermeable  to  sodium  and  potassium  ions,  but  per- 
meable to  chlorine  and  other  anions.  Hence  the  proportions  of 
alkali  to  chlorine,  etc.,  in  the  plasma  depend  upon  the  corpuscles, 
and  are  regulated  by  them  according  as  the  pressure  of  CO2  in 
the  blood  rises  or  falls.  Yandell  Henderson  and  Haggard,  who 
have  quite  recently  investigated  this  phenomenon  closely  from 
the  physiological  standpoint,  point  out  what  striking  effects  this 
regulating  action  may  produce.9  During  forced  breathing,  for 
instance,  the  weakly  combined  alkali  of  the  plasma  may  be  con- 
siderably diminished,  although  the  total  weakly  combined  alkali 
in  the  blood  need  not  necessarily  be  altered. 

The  relation  of  the  corpuscles  to  the  available  alkali  in  the 
plasma  suggests  at  once  the  question  whether  there  is  not  a  similar 
relation  as  regards  other  tissue  elements.  Henderson  and  Haggard 
showed  that  with  vigorous  and  continued  artificial  respiration 
the  available  alkali  in  the  whole  blood,  and  not  merely  in  the 
plasma,  diminishes  greatly,  and  that  this  diminution  is  accompa- 
nied by  signs  of  irretrievable  damage  to  the  body.  This  suggests 
excessive  draining  of  acid  from  the  tissue  elements  with  the 
result  that  the  whole  body  suffers,  although  the  alkalinity  of  the 
blood  itself  is  partly  prevented  from  falling.  The  matter  will, 
however,  be  discussed  further  in  Chapter  VIII. 

7  Giirber,  Sitz-der.  d.  physik-med.  Gesellsch.  zu  Wurzburg,  p.  28,   1895. 

Anionenwanderungen  in  serum  und  Blut  unter  den  einfluss  von  CO 2,  saure  und 
alkali.  Biochem.  Zett.  Vol.  86,  p.  309-324,  1918. 

9  Haggard  and  Henderson,  Journ.  of  Biol.  Chem.,  XLV,  p.  199,  1920. 


CHAPTER  VI 
The  Effects  of  Want  of  Oxygen. 

IN  the  higher  organisms,  as  Paul  Bert  first  pointed  out,  the  im- 
mediate cause  of  death  of  the  body  as  a  whole  is  practically  always 
want  of  oxygen,  owing  to  failure  of  the  circulation  or  breathing. 
This  fact  arises  from  the  circumstance  that  the  body  has  hardly 
any  internal  storage  capacity  for  oxygen,  but  depends  from 
moment  to  moment  for  its  supply  from  the  air.  We  can  deprive 
the  body  for  long  periods  of  its  external  supplies  of  food  or  water, 
or  we  can  prevent  for  some  time  the  excretion  of  urinary  products 
or  even  of  carbon  dioxide,  but  we  cannot  interfere  with  the  supply 
of  oxygen  to  the  blood  without  producing  at  once  the  most  threat- 
ening symptoms.  Almost  the  only  appreciable  storage  capacity 
for  surplus  oxygen  is  in  the  lungs.  In  virtue  of  this  small  store 
breathing  can  be  prevented  for  about  1*4  minutes  in  a  man  at 
rest  and  previously  breathing  normally  before  urgent  symptoms 
of  oxygen  want  appear ;  but  if  the  oxygen  in  the  lungs  and  blood 
is  rapidly  washed  out  by  breathing  pure  nitrogen,  nitrous  oxide, 
or  other  gas  free  from  oxygen,  loss  of  consciousness  occurs  almost 
at  once.  Lorrain  Smith  and  I  found  that  even  with  quiet  breathing 
of  pure  hydrogen,  so  that  some  time  was  needed  to  wash  out  the 
lungs,  sudden  and  complete  loss  of  consciousness  was  produced 
within  50  seconds. 

Even  when  the  oxygen  supply,  though  not  cut  off,  is  insuffi- 
ciently free,  the  ill  effects  develop  rapidly,  and  may  very  soon 
become  serious.  Hence  few  things  are  of  more  importance  in 
practical  medicine  than  the  causes  and  effects  of  want  of  oxygen. 

Want  of  oxygen  in  the  systemic  circulation  may  be  produced 
either  by  deficiency  in  the  available  oxygen  in  the  arterial  blood, 
or  by  abnormal  slowing  of  the  circulation,  so  that  too  much  of  the 
available  oxygen  is  used  up  in  the  systemic  capillaries.  It  will  be 
convenient  to  consider  first  the  effects  of  want  of  oxygen  or  "an- 
oxaemia," and  afterwards  discuss  the  various  ways  in  which  it 
may  be  produced. 

The  effects  of  anoxaemia  can  be  observed  most  conveniently  in 
persons  breathing  air  from  which  part  of  the  oxygen  has  been 
removed  without  the  addition  of  any  other  gas  producing  by 
itself  a  physiological  effect;  or  in  persons  breathing  pure  air  at 


RESPIRATION  109 

reduced  atmospheric  pressure.  In  either  case  the  partial  pressure 
of  the  oxygen  breathed  is  reduced,  and  the  haemoglobin  tends  to 
become  imperfectly  saturated  with  oxygen  in  the  lungs  in  cor- 
respondence with  the  dissociation  curve  for  the  oxygen  in  human 
blood  (Figure  20). 

The  effects  on  the  breathing  have  already  been  touched  upon 
in  Chapter  II,  but  must  now  be  discussed  fully.  In  most  persons 
the  percentage  of  oxygen  in  the  air  breathed,  or  the  barometric 
pressure,  must  be  reduced  by  about  a  third  before  any  evident 
effect  on  the  breathing  is  produced  at  the  time;  and  this  effect 
differs  according  as  the  reduction  is  produced  rapidly  or  slowly. 
With  a  greater  reduction  the  contrast  in  this  latter  respect  is  still 
more  marked.  With  rapid  reduction  there  is  at  first  a  quite  notice- 
able increase  in  the  depth,  and  also  in  the  frequency,  of  breathing. 
In  the  course  of  several  minutes,  however,  the  increase  diminishes 
markedly.  This  phenomenon  and  the  causes  of  it  were  described 
and  investigated  by  Poulton  and  myself.1  We  found  that  the  in- 
creased breathing  causes,  as  could  be  anticipated,  a  distinct  fall 
in  the  alveolar  CO2  pressure.  As  a  consequence,  more  CO2  than 
usual  is  washed  out  of  the  blood,  and  the  respiratory  quotient,  or 
ratio  of  the  volume  of  CO2  given  off  to  that  of  oxygen  absorbed, 
is  increased.  Thus  it  increased  from  the  normal  of  about  0.8  to  as 
much  as  2.8  when  there  was  sudden  and  considerable  oxygen  de- 
ficiency. Soon,  however,  the  extra  discharge  of  CO2  from  the 
blood  began  to  cease  and  there  was  only  a  slight  further  fall  in 
the  alveolar  CO2  pressure.  Part  passu  the  breathing  quieted  down 
so  as,  in  spite  of  the  diminished  discharge  of  CO2,  to  maintain  a 
certain  level  of  alveolar  CO2  pressure,  this  level  being  of  course 
below  the  normal  level.  At  the  same  time  the  alveolar  oxygen 
pressure  dropped,  since  the  lung  ventilation  had  diminished  while 
the  rate  of  absorption  of  oxygen  remained  undiminished.  The 
drop  in  alveolar  oxygen  pressure  tended,  of  course,  to  increase  the 
symptoms  of  want  of  oxygen  and  thus  prolong  the  period  of  in- 
creased breathing;  but  finally  a  balance  was  struck,  for  the  time 
at  any  rate.  When  the  deficiency  of  oxygen  was  produced  quite 
gradually  the  initial  marked  increase  of  breathing  was  not  notice- 
able, as  the  extra  CO2  was  washed  out  gradually. 

By  further  experiments,  we  found  that  the  new  and  lower 
level  of  alveolar  CO2  pressure  had  become  the  regulating  level 
for  the  atmosphere  breathed.  That  is  to  say,  a  small  increase  above 
this  level  caused  a  great  increase  in  the  breathing,  while  a  small 

*Haldane  and  Poulton,  Journ.  of  Physwl.,  XXXVII,  p.  390,  1908. 


1 10  RESPIRATION 

diminution  caused  apnoea,  just  as  when  pure  air  is  breathed.  It 
was  evident,  therefore,  that  the  CO2  pressure,  though  at  a  lower 
level,  was  controlling  the  breathing  still.  The  primary  marked 
increase  in  the  breathing  was  due  to  the  alveolar  CO2  pressure 
and  the  CO2  pressure  in  the  whole  of  the  body  being  above  the 
new  level,  and  the  quieting  down  of  the  breathing  was  due  to 
the  gradual  washing  out  of  CO2  from  the  whole  body  till  the  at- 
tainment of  the  new  normal  level,  which  was  itself  determined 
by  the  alveolar  oxygen  pressure. 

A  fuller  discussion  of  these  facts,  and  of  the  ultimate  physio- 
logical response  to  long-continued  slight  anoxaemia,  must  be 
postponed  to  Chapter  VII,  but  meanwhile  it  is  evident  that  they 
throw  a  new  light  on  the  physiology  of  breathing.  Hitherto  we 
have  considered  the  amount  of  lung  ventilation  as  if  it  were  de- 
termined solely  by  a  certain  excess  of  partial  pressure  of  CO2  in 
the  arterial  blood;  but  now  we  see  that  the  excess  is  something 
variable  and  dependent,  for  one  thing,  on  the  pressure  of  oxygen 
in  the  arterial  blood,  just  as  the  action  of  the  Hering-Breuer  re- 
flex depends,  not  merely  on  the  amount  of  distention  or  collapse 
of  the  lungs,  but  also  on  the  pressure  of  CO2  in  the  arterial  blood. 
Similarly  the  action  of  want  of  oxygen  on  the  breathing  depends 
on  the  CO2  pressure.  On  how  many  other  factors  which  together 
make  up  "normal  conditions"  the  action  of  CO2  or  want  of  oxy- 
gen on  the  respiratory  center  depends  we  do  not  know.  We  always 
find  normal  conditions  in  a  healthy  organism,  and  we  are  there- 
fore apt  to  overlook  their  unknown  complexity.  If  we  represented 
the  relation  between  arterial  CO2  pressure,  oxygen  pressure,  and 
lung  ventilation  in  the  form  of  an  equation,  this  equation  would 
only  be  valid  under  conditions  otherwise  normal.  In  other  words 
an  unknown  constant  C  would  have  to  be  set  down  in  the  equation. 

That  this  constant  exists  during  life — in  other  words  that  living 
organisms  maintain  fundamental  normals  of  structure  and  ac- 
tivity representing  the  <£™ris  of  Hippocrates — is  one  basis  of 
biological  science.  Apart  from  this  basis  physiology  would  be  a 
mere  chaos  of  unconnected  "bio-physical"  and  "bio-chemical" 
fragments. 

The  effect  produced  on  the  breathing  by  a  given  reduction  in 
the  oxygen  pressure  of  the  inspired  air  or  alveolar  air  varies  con- 
siderably in  different  individuals.  Some  respond  much  more 
readily  by  increased  breathing  than  others,  and  for  this  reason 
seem  to  be  better  protected  against  the  other  and  more  serious  ef- 
fects of  want  of  oxygen,  since  the  increased  breathing  raises  the  al- 


RESPIRATION  III 

veolar  oxygen  percentage.  In  some  persons  a  lowering  by  as  little 
as  5  per  cent  in  the  oxygen  percentage  of  the  inspired  air  will 
sensibly  increase  the  breathing,  but  in  most  persons  a  lowering  of 
at  least  7  per  cent  (i.e.,  from  20.94  to  14)  is  needed  to  produce  a 
measurable  effect,  while  in  others  very  little  effect  is  produced 
before  consciousness  is  lost  from  want  of  oxygen.  It  is  thus  for 
many  persons  peculiarly  dangerous  to  pass  into  an  atmosphere  in 
which  the  oxygen  percentage  is  very  low,  or  to  ascend  to  a  very 
great  height  in  a  balloon,  since  increased  breathing  may  give 
very  little  warning,  particularly  if  the  change  is  gradual,  so  that 
the  extra  CO2  is  blown  off  gradually. 

It  was  discovered  in  1908  by  Yandell  Henderson2  that  when 
effective  artificial  respiration  in  an  animal  has  been  pushed  to 
excess  for  some  time,  so  that  the  pressure  of  CO2  in  the  blood  and 
tissues  is  very  greatly  reduced,  there  is  not  only  a  prolonged 
succeeding  apnoea,  but  the  animal  dies  of  want  of  oxygen  without 
attempting  to  draw  a  single  breath.  The  artificial  respiration  must 
be  performed  somewhat  forcibly,  by  means  of  a  suction  and  ex- 
haust pump ;  and  the  reason  for  this  will  be  evident  from  what  has 
already  been  said  in  Chapter  III  as  to  the  control  of  the  chest- 
movements  by  the  Hering-Breuer  reflex  during  artificial  respira- 
tion produced  by  ordinary  means. 

This  important  experiment  shows  that  when  the  CO2  pressure 
is  reduced  below  a  certain  point  in  the  respiratory  center  the  latter 
ceases  to  respond  to  even  the  extremest  stimulus  of  want  of  oxy- 
gen. The  apnoea  produced  in  the  ordinary  way  by  voluntary 
forced  breathing  is  terminated,  as  shown  in  Chapter  V,  by  the 
combined  stimulus  of  CO2  and  want  of  oxygen,  and  in  some 
persons  the  oxyhaemoglobin  in  the  arterial  blood  runs  down  so 
low  that  the  lips  and  face  become  alarmingly  blue  before  breath- 
ing begins.  In  the  case  of  Poulton,  for  instance,  his  face  presented 
such  an  alarming  appearance  when  he  demonstrated  our  experi- 
ments at  a  meeting  of  the  Physiological  Society  that  one  or  two 
members  of  the  Society  could  hardly  be  restrained  from  applying 
artificial  respiration  on  the  spot.  In  my  own  case,  and  that  of  many 
others,  the  blueness  is  much  less  marked,  although,  as  already 
shown,  the  termination  of  the  apnoea  is  quite  clearly  due  to  want 
of  oxygen,  and  not  merely  to  accumulation  of  CO2. 

It  is  evident  from  the  foregoing  account  that  the  respiratory 
response  to  the  stimulus  of  uncomplicated  oxygen  want  is  a  com- 
plex one.  The  anoxaemia  tends  to  increase  the  breathing,  but  the 

'Yandell  Henderson,  Amer.  Journ.  of  Physiol.,  XXI,  p.  142,  1908. 


112  RESPIRATION 

increased  breathing,  by  washing  out  CO2,  checks  this  increase 
very  quickly,  so  that  the  net  result  for  the  time  is  only  a  small 
increase.  Where  the  anoxaemia  is  only  slight  this  net  increase  will 
be  practically  inappreciable,  and  this,  as  will  be  shown  in  Chap- 
ter VIII,  is  due,  not  to  the  fact  that  there  is  no  appreciable  anox- 
aemia, but  to  the  masking  of  the  natural  response  to  anoxaemia 
by  the  opposite  response  to  the  washing  out  of  CO2.  After  a  suffi- 
cient interval  of  time  the  former  response,  as  we  shall  see,  becomes 
unmasked  by  the  compensation  of  the  latter  response,  so  that  in 
the  long  run  there  is  a  very  definite  response  of  the  breathing  to 
even  a  very  small  fall  in  the  oxygen  pressure  of  the  inspired  air. 

When  diminution  in  the  oxygen  pressure  of  the  inspired  air  is 
accompanied  by  a  corresponding  increase  in  the  pressure  of  carbon 
dioxide,  it  is  evident  that  within  wide  limits  the  pressure  of  oxy- 
gen in  the  alveolar  air  will  remain  almost  normal,  since  the  in- 
creased breathing  due  to  the  extra  carbon  dioxide  will  so  raise 
the  alveolar  oxygen  pressure  as  to  compensate  approximately  for 
the  oxygen  deficiency  in  the  inspired  air.  There  will  thus  be  no 
appreciable  anoxaemia,  and  consequently  the  oxygen  deficiency 
in  the  inspired  air  will  produce  no  effect  at  all,  although  a  similar 
deficiency  in  the  absence  of  the  excess  of  CO2  would  produce  a 
marked  effect.  For  instance,  by  adding  CO2  to  the  inspired  air  we 
can  easily  compensate  within  wide  limits  for  the  deficient  oxygen 
pressure  which  affects  airmen  at  high  altitudes.  This  is  not  be- 
cause, as  Mosso3  imagined,  the  effects  of  high  altitude  are  due 
primarily  to  excessive  loss  of  CO2  ("acapnia"),  but  because  the 
oxygen  pressure,  as  well  as  that  of  CO2,  is  kept  approximately 
constant  by  the  increased  breathing  due  to  the  CO2.  When,  how- 
ever, the  conditions  are  such  that  the  extra  breathing  due  to  ex- 
cess of  CO2  does  not  prevent  the  alveolar  oxygen  pressure  from 
falling  very  low,  the  stimulus  of  anoxaemia  is  added  co  that  of 
CO2,  and  an  enormously  greater  effect  is  produced  on  the  breath- 
ing than  by  the  CO2  stimulus  alone.  This  extra  effect,  as  was 
recently  shown  by  Meakins,  Priestley,  and  myself4  is  due  to  in- 
crease in  the  frequency  of  the  breathing;  and  increased  frequency, 
provided  the  depth  of  breathing  is  sufficient,  is,  for  a  reason  which 
will  appear  in  the  next  chapter,  particularly  effective  in  prevent- 
ing anoxaemia. 

A  further  complication  in  the  effects  of  anoxaemia  and  forced 
breathing  on  the  respiratory  center  and  the  body  as  a  whole  is 

8  Mosso,  Life  of  Man  on  the  High  Alps,  Chapter  XXII,  London,  1898. 
4Haldane,  Meakins,  and  Priestley,  Journ,  of  Physiol.,  LII,  p.  420,  19 19. 


RESPIRATION  113 

introduced  by  the  fact  that,  as  Bohr  discovered  (see  Chapter  V 
and  Figure  19),  deficiency  of  carbon  dioxide  causes  haemoglobin 
to  hold  on  more  tightly  to  oxygen.  The  consequence  of  this  is,  that 
when  increased  breathing  lowers  the  pressure  of  CO2  in  the  al- 
veolar air  and  in  the  body  as  a  whole,  on  the  one  hand  the  haemo- 
globin of  the  blood  passing  through  the  lungs  is  more  highly 
saturated  with  oxygen  than  it  otherwise  would  be;  on  the  other 
hand  the  blood  holds  this  oxygen  so  firmly  that  the  oxygen  pres- 
sure in  the  tissues  falls  lower  than  it  otherwise  would.  There  may 
thus  be  considerable  anoxaemia  though  the  blood  is  almost  as  red 
as  usual,  and  the  existence  of  this  anoxaemia  is  only  revealed  by 
the  immediate  physiological  effects  of  raising  the  alveolar  oxygen 
pressure.5 

On  reducing,  in  a  steel  chamber,  the  atmospheric  pressure  to 
half  an  atmosphere  there  is  a  quite  appreciable  permanent  increase 
in  the  breathing,  and  consequent  drop  in  alveolar  CO2  pressure 
caused  by  anoxaemia,  but,  in  my  own  case  at  any  rate,  no  very 
striking  blueness  of  the  lips,  although  at  the  time  the  alveolar 
oxygen  pressure  is  only  about  34  mm.  This  pressure  would  only 
be  sufficient  to  saturate  the  oxyhaemoglobin  of  the  blood  to  the 
extent  of  57  per  cent  if  the  pressure  of  CO2  were  that  of  normal 
alveolar  air  (see  Figure  20).  Blood  with  this  percentage  satura- 
tion would  be  very  strikingly  blue.  Owing,  however,  to  the  dimin- 
ished pressure  of  CO2,  the  saturation  is  much  higher,  and  this 
accounts  for  the  color  of  the  lips  being  nearly  normal.  The  exist- 
ence of  considerable  anoxaemia  was,  however,  revealed  at  once 
by  the  effects  of  adding  oxygen  to  the  inspired  air :  for  vision  and 
hearing  were  at  once  strikingly  improved  and  the  breathing  di- 
minished. The  degree  of  blueness  of  the  lips  is  thus  only  a  rough 
index  of  anoxaemia  when  anoxaemia  is  taken  in  its  physiological 
meaning,  as  diminution  in  the  oxygen  pressure,  rather  than  merely 
of  the  oxygen  content,  of  the  blood.  It  is  the  diminution  in  the 
amount  of  free  oxygen,  whether  or  not  the  amount  of  reserve  oxy- 
gen combined  with  the  haemoglobin  is  also  diminished,  which  is 
functionally  important. 

Thus  the  benefit  produced  by  diminished  pressure  of  CO2  (as, 
for  example,  during  forced  breathing)  in  increasing  the  percent- 
age saturation  of  the  haemoglobin  in  the  arterial  blood  is  neu- 
tralized by  the  disadvantage  in  the  tissues  owing  to  the  same  cause. 
The  venous  blood  may,  in  fact,  be  as  red  as  usual,  although  the 
venous  oxygen  pressure  is  abnormally  low :  for  the  saturation  of 

*  Haldane,  British  Medical  Journal,  July  19,  1919. 


H4  RESPIRATION 

the  arterial  blood  with  oxygen  can  be  only  very  slightly  increased 
by  the  lowering  of  alveolar  CO2  pressure.  The  oxygen  pressure 
of  the  venous  blood  must  in  consequence  be  lowered,  so  that  anox- 
aemia might  be  produced  without  any  diminution,  and  even  with  a 
slight  increase,  in  the  saturation  of  the  haemoglobin  of  the  venous 
blood.  On  the  other  hand  if  the  haemoglobin  of  the  arterial  blood, 
with  normal  alveolar  CO2  pressure,  were  only  half-saturated,  a 
lowering  of  the  alveolar  CO2  pressure  would  considerably  in- 
crease the  saturation  of  the  haemoglobin  in  both  arterial  and 
venous  blood,  but  without  sensible  alteration  of  the  venous  oxygen 
pressure.  Only  in  the  practically  impossible  case  of  the  saturation 
of  the  arterial  haemoglobin  being  much  below  half  would  there 
be  any  rise  in  the  venous  oxygen  pressure.  Practically  speaking, 
therefore,  the  Bohr  effect,  the  increased  oxygen  content  in  blood, 
due  to  lowering  of  alveolar  CO2  pressure,  is  never  of  service  in 
increasing  the  real  oxygen  supply  to  the  tissues,  and  is  sometimes 
of  great  disservice,  although  it  always  tends  to  make  the  venous 
blood  less  blue,  and  so  diminishes  cyanosis.  On  the  other  hand  the 
corresponding  effect  due  to  raising  of  alveolar  CO2  pressure  will 
practically  never  diminish  the  oxygen  supply  to  the  tissues,  and 
will  usually  increase  it,  though  the  venous  blood  will  always  be 
more  blue. 

With  forced  breathing  of  normal  air  there  is,  as  mentioned  in 
Chapter  I,  a  slight  increase  in  the  oxygen  present  in  the  arterial 
blood.  This  is  due,  partly  to  the  Bohr  effect  and  partly  to  the  effect 
of  the  increased  alveolar  oxygen  pressure.  Hence  the  saturation 
of  the  haemoglobin  is  increased  from  about  95  to  100  per  cent. 
There  is  also  a  small  increase  in  the  free  oxygen  dissolved  in  the 
arterial  blood.  On  the  other  hand  the  amount  of  CO2  and  its 
partial  pressure  are  enormously  reduced  in  the  arterial  blood,  and 
to  a  less  extent  the  venous  blood,  since  the  circulation  rate,  as 
will  be  shown  in  Chapter  X,  is  much  diminished.  The  net  result 
must  be  a  considerable  fall  in  the  oxygen  pressure  in  the  tis- 
sues. Now  it  is  well  known  that  forced  breathing  produces  a 
train  of  symptoms  which,  if  the  forced  breathing  is  pushed, 
tend  towards  unconsciousness,  so  that  forced  breathing  has 
even  been  used  by  dentists  as  a  means  of  producing  partial 
anaesthesia.  In  many  respects  these  symptoms  are  similar  to  those 
of  anoxaemia,  except  for  the  absence  of  spontaneous  increased 
breathing.  It  was  discovered  by  Hill  and  Flack6  that  when  the 
forced  breathing  is  with  oxygen  instead  of  with  air  the  symptoms 

8  Hill  and  Flack,  Journ.  of  Physiol.,  XL,  p.  347,  1910. 


RESPIRATION  115 

are  greatly  diminished.  The  most  natural  explanation  of  this  is 
that  the  oxygen,  by  increasing  largely  the  amount  of  free  oxygen 
in  the  blood,  diminishes  the  anoxaemia,  since  an  oxygen  supply 
which  is  not  dependent  on  the  Bohr  effect  is  added  to  the  ordinary 
oxygen  supply  from  oxyhaemoglobin.  Probably,  therefore,  the 
symptoms  referred  to  are  mainly  produced  by  anoxaemia  caused 
by  the  Bohr  effect.  The  subject  will  be  discussed  further  in  Chap- 
ter X. 

It  is  a  very  interesting  fact  that  in  many  persons  forced  breath- 
ing does  not  produce  apnoea  at  all,  although  in  such  persons  the 
breathing  is  regulated  in  accordance  with  the  alveolar  CO2  pres- 
sure, just  as  in  other  persons.  This  fact  was  investigated  by  Dr. 
Boothby  some  years  ago  while  he  was  working  with  me.7  He 
found  that  at  the  end  of  continuous  forced  breathing  for  one  or 
two  minutes  there  was  in  himself  not  only  no  sign  of  apnoea,  but, 
on  the  contrary,  increased  natural  breathing  for  a  short  time.  This 
soon  passed  away,  but  at  no  time  was  there  any  apnoea,  though 
the  excretion  of  CO2  in  the  expired  air  was  much  diminished  for 
a  considerable  period.  The  cause  of  this  absence  of  apnoea  is  not 
yet  clear.  It  seemed  possible  that  the  stimulus  of  anoxaemia  from 
the  Bohr  effect  might,  in  persons  who  do  not  become  apnoeic, 
account  for  the  absence  of  apnoea ;  but  even  after  forced  breathing 
of  oxygen  the  apnoea  was  absent  in  one  of  these  persons  whom  I 
tested.  His  power  of  voluntarily  holding  a  deep  breath  was 
markedly  increased  by  forced  breathing  of  air,  but  natural  apnoea 
did  not  occur. 

Owing,  apparently,  to  the  existence  of  the  Bohr  effect,  the  in- 
fluence of  CO2  in  relieving  the  general  symptoms  of  anoxaemia 
is  not  due  merely  to  increased  breathing  and  consequent  rise  in 
the  alveolar  oxygen  pressure.  Lorrain  Smith  and  I  observed  that 
animals  in  a  semi-comatose  state  from  the  anoxaemia  of  carbon 
monoxide  poisoning  were  revived  by  substituting  expired  air  for 
pure  air  without  alteration  of  the  percentage  of  carbon  monoxide. 
With  the  expired  air  mixture  there  could  be  no  rise  in  the  alveolar 
oxygen  pressure,  and  there  was  no  alteration  in  the  percentage 
saturation  of  the  blood  with  carbon  monoxide.  A  still  more  strik- 
ing effect  is  produced  by  simply  adding  CO2  to  the  air  inspired 
during  CO  poisoning.  At  the  time  we  could  not  understand  this 
effect,  as  Bohr's  discovery  had  not  yet  been  made.  But  this  dis- 
covery furnishes  an  explanation  of  why  a  rise  in  the  alveolar  CO2 
pressure,  without  alteration  of  the  alveolar  oxygen  pressure, 

7  Boothby,  Journ.  of  PhysioL,  XLV,  p.  328, 


u6 


RESPIRATION 


should  relieve  the  symptoms  in  CO  poisoning :  for  the  increased 
CO2  pressure  will  enable  the  oxygen  to  come  off  more  easily  from 
the  oxyhaemoglobin  present  in  the  blood,  and  will  thus  tend  to 
relieve  the  anoxaemia.  The  circulation  rate  will  also  be  increased, 
as  will  appear  in  Chapter  X.  There  would  seem  to  be  a  considerable 
future  scope  for  the  therapeutic  use  of  CO2  in  anoxaemic  condi- 


|^- -vtlWA^^wvA/UlA/v^A/^vA/iJt^^ — J^\J\[lAAs*^sJ\jll\jy\~-~™l^ 


02   OFF 


Figure  37. 

Tracing  i.  (Stethograph)  Douglas,  July  12.  Evening  of  arrival  on  Pike's  Peak.  Natural 
periodic  breathing. 

Tracing  2.  Haldane,  July  12.  Evening  of  arrival.  Natural  periodic  breathing  with  more 
sharply  defined  periods  after  making  six  forced  breaths. 

Tracing  3.  July  16,  Haldane.  Natural  periodic  breathing  abolished  by  administration  of 
oxygen.  Reappearance  of  periodic  breathing  after  withdrawing  the  oxygen. 

tions  of  all  kinds,  whether  or  not  these  conditions  are  due  to  im- 
perfect oxygenation  of  the  arterial  blood. 

Even  when  simple  anoxaemia  is  so  extreme  that  consciousness 
is  on  the  point  of  being  lost,  the  breathing  in  man,  except  at  first, 
is  hardly  more  than  doubled,  as  shown  by  the  fact  that  the  alveolar 


RESPIRATION 


117 


CO2  pressure  is  only  reduced  to  about  half.  During  heavy  muscu- 
lar exertion,  on  the  other  hand,  the  breathing  may  easily  be  in- 
creased to  ten  or  fifteen  times  its  normal  amount.  The  relatively 
slight  increase  in  the  amount  of  air  breathed  during  very  serious 
anoxaemia  is  frequently  lost  sight  of  in  the  interpretation  of 
clinical  symptoms.  There  is  nearly  always  a  considerable  increase 
in  the  frequency  of  breathing,  but  the  depth  of  breathing  is 
usually  only  slightly  increased,  and  may  be  diminished,  as  will 
be  explained  more  fully  below.  In  the  very  dangerous  pure  anox- 
aemia of  high  altitudes  or  CO  poisoning,  increase  in  the  breathing 
is  not  a  prominent  symptom. 

It  has  been  known  for  long  that  at  high  altitudes  the  breathing 
is  very  apt  to  be  periodic.  This  phenomenon  was  fully  observed 
on  Monte  Rosa  by  Mosso,8  who,  however,  had  completely  failed 
to  realize  the  significance  of  Paul  Bert's  researches  on  the  effects 
of  gases,  and  thus  failed  to  interpret  correctly  the  cause  of  the 
periodic  breathing.  The  periodic  breathing  is  usually  not  con- 
tinuous, but  can  easily  be  started  by  disturbing  the  ordinary 
rhythm  of  breathing,  as  by  taking  a  few  long  breaths,  or  holding 
the  breath.  It  is  also  very  apt  to  occur  at  night.  It  is  distinguished 
from  ordinary  clinical  Cheyne- Stokes  breathing  by  the  shortness 


INTERVALS    OF     5    SECONDS 


Figure  38. 

Henderson,  August  13.  Quantitative  record  of  the  respiration  during  periodic 
breathing.  Inspiration  upwards. 

of  the  periods.  There  are  usually  groups  of  only  about  three  to 
six  breaths,  followed  by  a  pause,  and  this  periodic  sequence  con- 
tinues almost  indefinitely  (Figure  37).  Sometimes  the  middle 
breath  of  the  group  is  deepest,  sometimes  the  last  breath  (Figure 
38)  or  sometimes  the  breaths  are  about  equal  in  depth.  Some- 
times the  periodicity  only  shows  itself  by  periodically  recurring 
single  deep  breaths. 

The  general  explanation  of  this  periodic  breathing  has  already 
been  given  in  Chapter  V.  That  this  explanation  is  the  correct  one 
is  shown  by  the  fact  that,  as  is  seen  in  Figure  37,  on  adding  oxy- 

8  Mosso,  Life  of  Man  on  the  High  Alps,  Chapter  III,  London,   1898. 


n8 


RESPIRATION 


gen  to  the  inspired  air  the  periodicity  disappears.  This  experiment 
was  carried  out  repeatedly  by  Douglas,  Yandell  Henderson, 
Schneider,  and  myself,  on  Pike's  Peak,  and  never  failed.9  Mosso 
had  attempted  to  carry  it  out,  but  got  a  negative  result  owing  to  a 
defective  mode  of  administering  the  oxygen. 

As  already  seen  periodic  breathing  can  easily  be  produced  at 
ordinary  barometric  pressure  by  suitable  means.  As  the  barometric 
pressure  is  reduced  the  periodic  breathing  is  produced  more  and 
more  readily,  and  is  more  and  more  persistent,  just  as  might  be 
expected;  and  the  same  is  true  if,  instead  of  a  reduction  of  bar- 
ometric pressure,  there  is  a  reduction  in  the  oxygen  percentage  of 
the  inspired  air.  This  form  of  periodic  breathing  has  no  pathologi- 
cal significance,  and  occurs  during  perfect  health. 

The  special  characters  of  the  increased  breathing  caused  by 


Figure  39. 

(a)  Rebreathing — Concertina  filled  with  oxygen — CO*  accumulating, 

(b)  Rebreathing — Concertina  filled  with  air — CO2  accumulating. 
Time-marker  =  2  seconds.  Arrow  shows  point  where  lips  were  distinctly  blue. 

anoxaemia  were  recently  studied  by  Meakins,  Priestley,  and 
myself.10  The  differences  between  increased  breathing  caused  by 
excess  of  CO2  and  that  caused  by  anoxaemia,  or  by  anoxaemia 
accompanied  by  excess  of  CO2,  are  very  striking.  Speaking  gen- 
erally, the  effect  of  excess  of  CO2  is  mainly  to  increase  the  depth 
of  breathing,  and  only  a  moderate  increase  of  frequency  is  pro- 
duced. On  the  other  hand  anoxaemia  produces  a  marked  increase 
in  frequency  and  only  a  moderate  increase  in  depth.  But  when  the 

*  Douglas,  Haldane,  Yandell  Henderson,  and  Schneider,  Philos.  Trans.  Royal 
Society,  B.  203,  p.  231. 

"Meakins,  Haldane,  and  Priestley,  Journ.  of  Physiol.,  LII,  p.  420,  1919. 


RESPIRATION 


119 


effects  of  excess  of  CO2  and  anoxaemia  are  combined  there  is 
great  increase  of  both  depth  and  frequency,  so  that  far  more  air  is 
breathed  than  when  either  excess  of  CO2  alone,  or  anoxaemia 
alone,  is  the  stimulus.  In  my  own  case,  for  instance,  when  the 
breathing  was  pushed,  in  short  experiments,  to  as  much  as  seemed 
bearable,  131  liters  per  minute,  with  a  depth  of  1.98  liters  and  a 
frequency  of  66  per  minute,  were  breathed  when  the  effects  of 
excess  of  CO2  and  anoxaemia  were  combined ;  and  only  8 1  liters, 
with  a  depth  of  2.69  and  a  frequency  of  30,  when  the  only  stimulus 
was  excess  of  CO2. 

Figure  39  shows  quantitatively  the  effects  of  rebreathing  a 
small  volume  (about  2  liters)  of  air  or  oxygen  from  the  recording 
concertina  already  described.  It  will  be  seen  that  the  increase  in 
frequency  was  much  less  when  the  effects  of  anoxaemia  were  cut 
out  by  the  oxygen. 

Figure  40  A  shows  the  effect  on  the  same  subject  of  similar  re- 
breathing  when  the  accumulation  of  CO2  was  prevented  by  inter- 


iiiiiii.ini 


Figure  40. 

Rebreathing   through   soda-lime   from   concertina.    Time-marker  =  2   seconds, 
(a)  Subject  Cpl.  M.  (b)  Subject  J.  S.  H. 

posing  a  layer  of  soda  lime.  It  will  be  seen  that  the  frequency 
increases,  but  not  the  depth.  Figure  40  B  shows  the  effects  on 
another  subject,  whose  respiratory  center  responds  much  more 
readily  to  the  effects  of  anoxaemia.  In  this  case  depth  as  well  as 
frequency  are  considerably  increased.  It  must,  however,  be  borne 
in  mind  that,  in  short  experiments  such  as  these,  the  increased 
breathing,  as  already  explained,  is  mainly  due  to  the  necessity  of 


-E 


* 


o 

t~t 

W> 

I 


E-8 


RESPIRATION  121 

removing  from  the  body  the  large  amount  of  preformed  CO2 
which  has  become  superfluous  owing  to  the  effect  of  anoxaemia 
in  lowering  the  threshold  of  CO2  pressure. 

Figures  41  and  42  show  the  effects  of  anoxaemia  combined  with 
those  of  the  slight  resistance  associated  with  the  recording  ap- 
paratus. The  effects  are  complicated  owing  to  the  fact  that  with  a 
certain  degree  of  anoxaemia,  varying  greatly  for  different  indi- 
viduals, periodic  breathing  is  produced  readily,  as  shown  in  some 
of  the  tracings.  Periodic  breathing,  or  else  very  shallow  breathing, 
is  also  produced  invariably  after  the  anoxaemia,  as  shown  in  all 
the  tracings.  This  is  of  course  due  to  the  fact  that  so  much  CO2 
has  been  removed  from  the  body  by  the  hyperpnoea  of  anoxaemia, 
just  as  it  is  removed  by  forced  breathing. 

In  Figure  41  B  and  Figure  42,  A,  C,  and  D,  it  will  be  seen  that 
after  an  initial  increase  in  depth  the  breathing  became  progres- 
sively shallower  and  more  frequent  just  as  in  fatigue  due  to  ex- 
cessive resistance;  and  after  a  time  asphyxial  symptoms  were 
usually  impending  owing  to  the  ineffectiveness  of  the  shallow 
breaths.  When  the  experiments  were  made  we  had  not  investigated 
the  effects  of  fatigue  caused  by  resistance,  and  there  is  now  no 
doubt  that  the  slight  resistance  due  to  the  apparatus,  combined 
with  the  effects  of  anoxaemia  on  the  respiratory  center,  accounted 
for  the  specially  rapid  failure  of  breathing  shown  in  the  figures. 
When  the  breathing  is  quite  free,  as  in  a  steel  chamber  at  low 
pressures,  failure  of  the  respiratory  center  does  not  occur  nearly 
so  readily,  but  the  difference  is  only  one  of  degree;  and  failure 
of  the  respiratory  center,  as  shown  by  shallow  and  frequent  res- 
pirations, is  the  inevitable  result  of  serious  arterial  anoxaemia. 
With  the  increasing  shallowness  of  the  breaths  the  arterial  an- 
oxaemia increases,  owing  to  causes  discussed  in  Chapter  VII. 
This  increases  the  failure  of  the  respiratory  center;  and  unless 
relief  comes  the  inevitable  result  of  the  vicious  circle  thus  pro- 
duced is  death. 

We  must  now  turn  to  the  other  symptoms  and  signs  of  want  of 
oxygen,  beginning  with  the  circulatory  symptoms.  Unfortunately 
we  cannot  as  yet  measure  the  volume  of  blood  circulated  per 
minute  in  the  same  easy  way  in  which  we  can  measure  the  volume 
of  air  breathed.  Our  knowledge  of  the  effects  of  want  of  oxygen 
on  the  circulation  is  thus  imperfect  as  yet.  It  will  be  discussed 
more  fully  in  Chaper  X.  When  moderate  symptoms  of  anoxaemia 
are  produced  experimentally,  as  in  a  steel  chamber  at  reduced 
atmospheric  pressure,  or  when  air  deficient  in  oxygen  is  breathed, 


RESPIRATION 


123 


there  is  at  first  an  increase  of  the  frequency,  and  apparently  also 
in  the  strength,  of  the  heartbeats.  This  indicates  an  increase  in  the 
circulation  rate.  But  just  as  in  the  case  of  the  respirations,  the 
frequency  and  vigor  of  the  pulse  soon  fall  again,  though  the  fre- 
quency remains  above  normal,  just  as  does  the  frequency  of  res- 
piration. Thus  the  pulse  may  rise  to  about  120  at  first,  and  then 
fall  after  a  few  minutes  to  about  90,  and  remain  steady.  With 
greater  anoxaemia  the  increase  in  rate  is  more  marked.  The  great 
temporary  increase  in  blood  pressure  with  acute  anoxaemia  in 
animals  is  also  a  well-known  phenomenon. 

At  first  sight  it  might  seem  that  a  great  increase  in  both  res- 
pirations and  circulation  would  be  the  natural  physiological 
response  to  anoxaemia,  since  the  increased  respiration  will  raise 
the  alveolar  oxygen  pressure  and  the  increased  circulation  rate 
will  increase  the  amount  of  oxygen  left  in  the  red  corpuscles  of 
the  blood  passing  through  the  capillaries.  But,  as  already  seen, 
the  increased  respiration  lowers  the  pressure  of  CO2  in  the  respira- 
tory center  and  tissues,  and  this  lowering  rapidly  reduces  the  in- 
creased breathing  to  within  relatively  narrow  limits.  A  similar 
lowering  of  CO2  pressure  in  the  tissues  must  also  be  produced  by 
increased  circulation  rate ;  and  the  f  alling-off  in  the  initial  increase 
of  pulse  rate  is  probably  at  bottom  due  to  the  same  cause  as  the 
falling-off  in  the  initial  depth  and  frequency  of  breathing.  With 
further  increase  in  the  anoxaemia  the  heartbeats,  like  the  respira- 
tions, become  more  and  more  feeble.  A  fuller  discussion  of  the 
relatively  little  that  is  at  present  known  definitely  as  to  the  physio- 
logical regulation  of  the  circulation  will  be  found  in  Chapter  X. 
It  is  of  course  evident  that  the  physiology  (not  the  mere  physics) 
of  the  circulation  is  intimately  related  to  that  of  the  breathing. 

As  a  sign  of  anoxaemia,  the  appearance  of  the  lips,  tongue,  and 
face  is  of  much  importance,  but  requires  careful  interpretation. 
The  bluish  color  or  cyanosis  seen  in  the  lips  and  skin  during 
ordinary  anoxaemia  is,  of  course,  due  to  the  fact  that  in  the  blood 
passing  through  the  capillaries  the  proportion  of  oxyhaemoglobin 
to  haemoglobin  is  abnormally  low.  A  somewhat  similar  color  may 
be  produced  by  the  action  of  poisons  which  produce  methaemo- 
globin  and  other  colored  decomposition  products  in  the  blood; 
and  this  condition,  which  is  of  course  quite  exceptional,  and  can 
quite  easily  be  distinguished,  will  be  referred  to  in  Chapter  VII. 
Cyanosis  may  either  be  due  to  general  or  local  slowing  of  the 
circulation,  or  to  the  fact  that  the  arterial  blood  is  imperfectly 
oxygenated,  and  the  latter  cause,  as  will  be  shown  in  Chapter  VII, 


124  RESPIRATION 

is  far  more  common  than  was,  till  recently,  supposed.  Portions  of 
the  skin  may  be  blue  from  local  slowing  of  the  circulation  due  to 
cold  and  other  causes;  but  abnormal  blueness  of  the  lips  and 
tongue  points  to  either  imperfect  oxygenation  of  the  arterial 
blood  or  general  slowing  of  circulation.  According  as  there  is 
much  or  little  blood  in  the  capillaries  the  color  is  full  or  unsatu- 
rated.  Thus  in  extreme  cyanosis  the  lips  may  be  either  almost 
black,  or  only  leaden  gray ;  and  in  slight  cyanosis  the  color  may 
be  either  a  full  or  a  pale  purplish  red. 

Ordinary  cyanosis  of  one  kind  or  another  is  commonly  seen  in 
patients  who,  though  suffering  from  some  chronic  ailment,  are 
not  particularly  ill.  Hence  the  significance  of  cyanosis  under  other 
conditions  is  apt  to  be  overlooked  unless  all  the  symptoms  and 
other  circumstances  are  taken  into  account.  It  must,  in  the  first 
place,  be  pointed  out  that  the  degree  of  cyanosis  is  no  direct 
measure  of  the  degree  of  physiological  anoxaemia.  The  latter  is 
due  to  a  lowering  in  the  partial  pressure  of  oxygen  in  the  blood  of 
the  capillaries,  while  the  former  is  due  to  a  diminution  in  the  ratio 
of  oxyhaemoglobin  to  haemoglobin.  Under  ordinary  conditions 
the  latter  effect  is  an  index,  though,  owing  to  the  form  of  the 
dissociation  curve  of  oxyhaemoglobin  (Figure  20),  not  a  direct 
measure,  of  the  former  effect.  When,  however,  the  matter  is  com- 
plicated by  an  alteration  in  the  Bohr  effect  of  CO2  pressure  on  the 
dissociation  of  oxyhaemoglobin,  the  relationship  between  oxygen 
pressure  and  dissociation  of  oxyhaemoglobin  is  at  once  altered.  If, 
for  instance,  the  pressure  of  CO2  in  the  arterial  blood  is  reduced 
by  increased  breathing,  there  may  be  much  less  cyanosis  for  a 
given  degree  of  physiological  anoxaemia  than  when  the  CO2 
pressure  in  the  blood  is  normal.  Thus  there  is  no  fixed  relationship 
between  cyanosis  and  physiological  anoxaemia;  and  this  fact  is 
of  great  importance  in  the  clinical  interpretation  of  cyanosis. 
Moreover,  as  Barcroft  showed,  the  Bohr  effect  is  due  to  the  action 
of  CO 2  as  an  acid.  Hence,  owing  to  the  adjustments  which,  as  will 
be  shown  in  Chapter  IX,  occur  in  the  living  body  when  time  is 
given,  the  CO2  pressure  in  the  alveolar  air  may  be  no  guide  as  to 
how  far  the  Bohr  effect  is  disturbing  the  ordinary  relations  be- 
tween cyanosis  and  true  anoxaemia.  The  word  "anoxaemia" 
should  evidently  be  taken  as  signifying  a  condition  in  which  the 
free  oxygen  in  the  systemic  capillary  blood  is  abnormally  dimin- 
ished ;  and  this  of  course,  in  accordance  with  Henry's  law,  comes 
to  the  same  thing  as  diminution  in  the  oxygen  pressure. 

The  symptoms  produced  in  the  nervous  system  generally  by 


RESPIRATION  125 

anoxaemia  must  now  be  described.  A  knowledge  of  them  is  of 
great  importance  in  practical  medicine.  If  a  pure  anoxaemia  is 
produced  very  suddenly,  as  by  breathing  pure  nitrogen,  hydro- 
gen, methane,  or  nitrous  oxide,  loss  of  consciousness  occurs  quite 
suddenly  and  with  no  previous  warning  symptoms.  Thus  a  miner 
who  puts  his  head  into  a  cavity  in  the  roof  full  of  pure,  or  nearly 
pure,  methane  drops  suddenly  as  if  he  had  been  felled ;  and  when 
he  recovers  after  breathing  pure  air  for  a  few  seconds  he  some- 
times even  imagines  that  he  has  been  knocked  down  by  another 
man,  and  acts  accordingly.  If  the  anoxaemia  is  produced  with 
only  moderate  rapidity  the  marked  temporary  disturbances,  al- 
ready referred  to,  in  the  breathing  and  circulation  give,  as  a  rule, 
some  warning  of  what  is  coming.  But  when  the  onset  is  gradual 
there  is  little  or  no  preliminary  discomfort,  and  for  this  reason 
the  onset  of  pure  anoxaemia  is  very  insidious,  and  the  condition 
is,  therefore,  in  practice  a  dangerous  one,  as  is  well  seen  in  CO 
poisoning,  or  in  ascents  to  very  high  altitudes  in  balloons  or  aero- 
planes, or  in  many  clinical  cases.  Thus  although  CO  is  not  very 
poisonous  as  compared  with  other  gaseous  poisons,  it  is  responsible 
for  a  far  larger  number  of  deaths  than  any  other  gaseous  poison 
not  used  in  warfare. 

As  the  slow  onset  of  anoxaemia  advances,  the  senses  and  intellect 
become  dulled  without  the  person  being  aware  of  it;  and  if  the 
anoxaemia  is  suddenly  relieved  by  means  of  oxygen  or  ordinary 
air,  the  corresponding  sudden  increase  in  powers  of  vision,  hear- 
ing, etc.,  is  an  intense  surprise.  The  power  of  memory  is  affected 
early,  and  is  finally  almost  annulled,  so  that  persons  who  have  ap- 
parently never  lost  consciousness  can  nevertheless  remember  noth- 
ing of  what  has  occurred.  Powers  of  sane  judgment  are  much 
impaired,  and  anoxaemic  persons  become  subject  more  or  less  to 
irrational  fixed  ideas,  and  to  uncontrolled  emotional  outbursts. 
Muscular  coordination  is  also  affected,  so  that  a  man  cannot  walk 
straight  or  write  steadily.  With  further  increase  in  the  anoxaemia, 
power  over  the  limbs  is  lost;  the  legs  first  being  paralyzed,  then 
the  arms,  and  finally  the  head.  The  senses  are  lost  one  by  one,  hear- 
ing being  apparently  the  last  to  go.  The  sense  of  painful  impres- 
sions on  the  skin  seems  to  be  lost  early.  Thus  miners  suffering  from 
CO  poisoning,  but  not  to  the  point  of  losing  consciousness,  are 
often  burnt  by  their  lamps  or  candles  without  their  being  aware  of 
the  burn  at  the  time. 

In  many  respects  the  symptoms  of  anoxaemia  resemble  those 
of  drunkenness,  and  a  man  suffering  from  anoxaemia  cannot  be 


126  RESPIRATION 

held  responsible  for  his  actions.  Without  reason  he  may  begin  to 
laugh,  shout,  sing,  burst  into  tears,  or  become  dangerously  violent. 
He  is,  however,  always  quite  confident  that  he  himself  is  perfectly 
sane  and  reasonable,  though  he  may  notice,  for  instance,  that  he 
cannot  walk  or  write  properly,  cannot  remember  what  has  just 
happenedx  and  cannot  properly  interpret  his  visual  impressions. 
When  unable  even  to  stand,  owing  to  experimental  CO  poisoning 
or  to  anoxaemia  produced  by  low  pressures  in  a  steel  chamber,  I 
have  always  been  quite  confident  in  my  own  sanity,  and  it  was 
only  afterwards  that  I  realized  that  I  could  not  have  been  in  a 
sane  state  of  mind. 

A  recent  experience  of  this  kind  was  in  a  steel  chamber  in  which 
Dr.  Kellas,  who  is  an  experienced  climber  in  the  Himalayas  and 
has  exceptional  powers  of  resisting  anoxaemia,  was  with  me.11 
We  had  reduced  the  pressure  to  320  mm.,  and  as  I  could  no  longer 
write  or  make  any  observations  I  handed  him  the  notebook.  He 
afterwards  told  me  that  I  remained  sitting,  but  always  answered 
his  questions  quite  deliberately  and  confidently,  and  insisted  on 
his  keeping  the  pressure  at  320  mm.  This  went  on  for  an  hour  and 
a  quarter,  of  which  time  I  could  afterwards  remember  absolutely 
nothing.  At  last  Dr.  Kellas  obtained  my  assent  to  raising  the  pres- 
sure to  350  mm.,  after  which  I  took  up  a  mirror  to  look  at  my  lips, 
though  Dr.  Kellas  observed  that  for  some  time  I  looked  at  the 
back  instead  of  the  front  of  the  mirror.  I  had,  however,  begun  to 
realize  that  we  had  been  far  longer  at  the  low  pressure  than  we 
had  intended,  and  agreed  to  a  rise  to  450  mm.  On  reaching  this 
pressure  my  mind  had  cleared  and  I  noticed  a  return  of  feeling 
and  power  in  my  legs.  After  coming  out  I  could  vaguely  remember 
taking  up  the  mirror,  but  nothing  before  that,  after  handing  over 
the  notebook.  We  had  no  intention  of  staying  at  so  low  a  pressure 
that  it  was  impossible  for  me  to  take  notes,  and  my  persistence 
was  quite  irrational.  Dr.  Kellas  was  much  bluer  than  I  was  during 
the  stay  at  320  mm.,  but  could  still  write  quite  well,  watch  the  ba- 
rometer, and  manage  the  regulating  tap ;  but  whether  he  was  quite 
normal  mentally  seemed  rather  doubtful.  Perhaps  he  shared  to 
some  extent  my  irrational  desire  to  continue  the  experiment: 
otherwise  I  think  he  would  have  noticed  how  abnormal  my  condi- 
tion was.  We  were  both  at  the  time  unacclimatized  to  low  pres- 
sures. 

This  personal  experience  illustrates  some  of  the  peculiar 
dangers  associated  with  atmospheres  which  produce  anoxaemia, 

11  Haldane,  Kellas,  and  Kennaway,  Journ.  of  Physiol.,  LIII,  p.  181,  1919. 


RESPIRATION  127 

whether  in  virtue  of  defective  oxygen  pressure  or  of  the  presence 
of  poisonous  proportions  of  CO.  In  the  first  place  it  is  evident  that 
a  man  may  advance  for  some  distance  into  such  an  atmosphere 
before  he  begins  to  be  seriously  affected;  for  the  temporary 
marked  increase  in  the  breathing  may,  when  the  oxygen  pressure 
is  defective,  at  first  prevent  an  appreciable  fall  in  the  alveolar 
oxygen  pressure.  This  must,  for  instance,  happen  while  a  balloon 
or  aeroplane  is  rising  rapidly,  or  while  a  miner  is  advancing  with 
an  electric  lamp  into  an  atmosphere  very  highly  charged  with 
fire-damp.  When  the  breathing  begins  to  quiet  down  again  the 
effects  of  the  atmosphere  will  develop  fully  and  it  may  then  be  too 
late  to  turn.  At  320  mm.,  for  instance,  I  was  at  first  quite  capable 
of  making  observations  and  taking  notes,  including  a  note  of  the 
increased  breathing  and  its  subsequent  quieting  down. 

Another,  and  often  still  more  serious,  danger  arises  from  the 
gradual  and  insensible  failure  of  judgment.  A  man  suffering  from 
anoxaemia  will  usually  go  on,  and  insist  in  going  on,  with  what 
he  set  out  to  do.  An  airman  will  very  probably  continue  to  ascend, 
oblivious  to  danger ;  and  a  miner  engaged  in  rescue  or  exploration 
work,  or  in  dealing  with  an  underground  fire,  will  insist  in  going 
on  when  he  is  suffering  from  the  anoxaemia  of  CO  poisoning, 
and  will  often  fight  any  one  who  tries  to  make  him  desist. 

All  these  considerations  apply  equally  to  clinical  cases  of  anox- 
aemia ;  and  for  this  reason  the  condition  is  quite  commonly  never 
recognized  till  too  late.  The  early  recognition  of  clinical  anox- 
aemia is  a  matter  of  great  importance. 

Besides  the  immediate  symptoms  of  anoxaemia  there  are  a 
number  of  delayed  symptoms  or  after  effects.  They  depend  partly 
on  the  length,  and  partly  on  the  severity,  of  the  exposure.  A 
short  exposure,  even  with  loss  of  consciousness,  produces  no 
serious  after  symptoms ;  but  occasionally  a  man's  behavior  is  very 
abnormal  for  a  few  minutes  after  recovery.  One  of  my  ac- 
quaintances has  twice  knocked  persons  down  on  waking  up  from 
a  short  loss  of  consciousness  caused  by  anoxaemia;  and  my  own 
behavior  was  distinctly  abnormal  just  after  coming  out  from  the 
steel  chamber  in  the  experiment  alluded  to  above.  Similar  ab- 
normalities after  slight  CO  poisoning  have  often  come  under  my 
observation.  Thus  a  well-known  inspector  of  mines,  on  returning 
to  the  surface  after  he  had  been  affected  by  CO  from  an  under- 
ground fire,  first  shook  hands  very  cordially  with  all  the  by- 


128  RESPIRATION 

standers.  A  doctor  who  was  present  then  offered  him  an  arm ;  but 
this  the  inspector  regarded  as  an  insult,  with  the  result  that  he 
took  off  his  coat  and  challenged  the  doctor  to  a  fight. 

The  best-known  delayed  effect  of  slight  anoxaemia  is  the  train 
of  symptoms  originally  called  "mountain  sickness."  This  is  a 
condition  in  the  typical  form  of  which  there  is  nausea,  vomiting, 
headache,  sometimes  diarrhoea,  and  always  great  depression.  The 
symptoms  appear,  as  a  rule,  some  hours  after  the  beginning  of 
the  exposure,  and  may  not  appear  at  all  till  after  the  exposure  is 
over.  In  CO  poisoning  it  is  usually  after  the  exposure,  and  often 
after  the  CO  has  practically  disappeared  from  the  blood,  that 
these  symptoms  begin.  The  duration  of  exposure  required  for  their 
production  depends  upon  the  degree  of  anoxaemia.  Thus  the 
higher  a  mountain  is,  or  the  greater  the  altitude  at  which  an  air- 
man has  been  flying,  the  shorter  is  the  exposure  required.  On 
Pike's  Peak,  at  14,100  feet  (barometer  about  458  mm.)  the  usual 
stay  (an  hour  or  two)  of  visitors  by  train  is  too  short  to  produce 
mountain  sickness,  though  the  ordinary  immediate  symptoms  of 
anoxaemia  are  usually  very  evident,  and  even  very  great  cyanosis 
and  fainting  are  observed  occasionally.  A  stay  of  several  hours 
is  usually  required  to  induce  mountain  sickness,  which  usually 
begins  about  8  to  12  hours  after  the  beginning  of  the  exposure. 
Thus  the  symptoms  may  only  develop  after  the  return  downwards. 

With  a  sufficient  period  of  exposure  mountain  sickness  may 
develop  at  much  lower  altitudes  than  that  of  Pike's  Peak.  It  is 
often  observed  at  even  7,000  or  8,000  feet,  where  the  degree  of 
anoxaemia  is  not  sufficient  to  produce  any  noticeable  immediate 
effect  on  the  breathing.  Similarly  a  percentage  of  CO  which  pro- 
duces no  noticeable  immediate  effect  will,  with  sufficiently  long 
exposure,  cause  headache,  nausea,  etc.  These  facts  are  of  the 
greatest  significance  in  clinical  medicine,  for  it  is  now  evident  that 
even  a  very  slight  degree  of  continued  anoxaemia  is  of  much 
importance  to  the  patient.  Mountain  sickness  and  the  effects  of 
CO  poisoning  are  not  isolated  phenomena  unrelated  to  the  rest  of 
physiology  and  pathology,  but  symptoms  of  anoxaemia,  which  is 
in  reality  one  of  the  commonest  conditions  during  illness.  At 
present  we  can  only  conjecture  as  to  the  nature  of  the  slight 
temporary  pathological  changes  of  which  the  mountain  sickness 
symptoms  are  the  manifestations. 

With  severe  and  prolonged  exposure  to  want  of  oxygen  the 
nervous  after  symptoms  are  of  an  extremely  formidable  nature, 


RESPIRATION  129 

and  often  end  in  death.12  For  a  reason  which  will  be  explained 
in  a  later  chapter  they  are  most  commonly  met  with  after  CO 
poisoning,  and  whatever  their  origin  they  are  often  grossly  mis- 
interpreted. The  patient  does  not  recover  at  once  on  removal  of 
the  oxygen  want,  as  in  short  exposures.  In  cases  of  CO  poisoning 
consciousness  may  not  be  recovered,  although  within  an  hour  or 
two  after  removal  to  fresh  air  most  of  the  CO  has  already  disap- 
peared from  the  blood.  It  is  exactly  the  same  with  men  who  have 
remained  unconscious  for,  perhaps,  several  hours  in  air  very  poor 
in  oxygen.  Or  if  consciousness  has  been  partially  recovered  the 
patient  may  lapse  again  into  unconsciousness.  During  gradual 
recovery  there  is  usually  a  very  marked  spastic  condition  of  the 
muscles,  and  occasional  epileptiform  seizures,  and  there  may  be 
various  partial  paralyses  and  other  nervous  symptoms.  Sometimes 
the  patient  lingers  on  for  weeks  in  a  comatose  condition  with 
spastic  muscles  and  occasional  opisthotonos.  The  body  tempera- 
ture is  unstable,  and  every  function  of  the  central  nervous  system 
seems  to  be  more  or  less  affected.  Gross  hemorrhages  in  the  brain 
have  been  described,  and  Mott  has  found  small  multiple  hemor- 
rhages. The  symptoms  are,  however,  evidently  due  in  the  main 
to  widespread  injury  to  the  nerve  cells  themselves  during  the  ex- 
posure. Loss  of  memory,  mental  incapacity,  and  even  definite 
mania  may  follow  the  exposure;  but  whatever  the  nature  of  the 
symptoms  may  be,  they  nearly  always  pass  off  gradually  if  the 
patient  survives  the  first  few  days.  One  interesting  nervous  after 
effect  occasionally  observed  is  what  appears  from  the  symptoms 
to  be  peripheral  neuritis. 

The  heart  may  also  suffer  severely  in  prolonged  exposure  to 
want  of  oxygen ;  and  if  the  exposure  has  been  accompanied  by 
much  muscular  exertion,  as  in  efforts  to  escape  or  to  rescue  other 
men,  the  after  symptoms  may  be  mainly  cardiac.  In  these  cases 
the  pulse  is  feeble  and  irregular,  the  heart  dilated,  with  a  blowing 
systolic  murmur;  and  any  muscular  exertion  produces  collapse.  It 
may  be  a  considerable  time  before  the  heart  fully  recovers. 

Probably  every  other  organ  and  tissue  in  the  body  feels  the 
after  effects  of  severe  exposure  to  want  of  oxygen.  The  patient 
often  enough  dies  of  pneumonia.  Acute  nephritis  and  gangrene  of 
extremities  have  been  noticed  as  sequelae  to  the  acute  broncho- 
pneumonia  and  oedema  of  the  lungs  in  chlorine  poisoning.  As 

"  An  interesting  description  of  these  symptoms  by  Dr.  Shaw  Little  will  be 
found  in  Appendix  B  to  my  Report  on  the  Causes  of  Death  in  Colliery  Explosions, 
Parliamentary  Paper  C.  8112,  1896. 


1 30  RESPIRATION 

the  patients  have  been  exposed  to  very  grave  oxygen  want  in 
consequence  of  the  lung  condition,  it  seems  probable  that  the  af- 
fections just  mentioned  are  after  effects  of  the  oxygen  want, 
aggravated  by  the  after  effects  on  the  heart,  and  often  complicated 
by  secondary  infections. 

With  anoxaemia,  as  already  explained,  the  respiratory  center 
becomes  very  easily  susceptible  of  fatigue,  as  manifested  by  di- 
minishing depth  of  the  breathing.  It  is  now  well  known  that  in 
the  resuscitation  of  persons  who  have  been  nearly  asphyxiated  by 
drowning,  asphyxiating  atmospheres,  etc.,  the  most  effective 
remedy  is  artificial  respiration.  This  is  because  the  respiratory 
center  has  completely  or  almost  completely  failed  or  become 
"fatigued,"  and  the  patient  would  die  if  this  condition  were  not 
compensated  for  by  artificial  respiration.  Respiration  seems  almost 
always  to  fail  before  the  heart  fails.  The  respiratory  center  may 
also  take  a  long  time  to  recover  sufficiently  to  be  able,  without 
artificial  aid,  to  keep  the  patient  alive.  For  this  reason  it  may  be 
necessary  to  prolong  the  artificial  respiration  for  hours. 

Diminishing  depth  with  increasing  rate  of  respiration  is  always 
a  sign  of  the  onset  of  fatigue  of  the  breathing;  and  when  the 
depth  continues  to  diminish  without  compensation  from  increased 
rate  the  condition  rapidly  becomes  dangerous,  as  will  be  shown 
in  Chapter  VII,  since  secondary  anoxaemia  develops.  In  a  person 
dying  quietly  the  diminishing  depth  can  be  observed  until  the 
resulting  anoxaemia  ends  in  death.  The  immediate  cause  of  death 
seems  to  be  failure  of  the  respiratory  center.  When  death  from 
anoxaemia  occurs  at  very  high  altitudes  (as,  for  instance,  in  the 
case  referred  to  in  Chapter  XII,  of  the  balloonists,  Tissandier  and 
Croce  Spinelli)  it  is  evidently  failure  of  the  respiratory  center 
which  precipitates  the  anoxaemia,  thus  making  the  conditions 
so  very  dangerous ;  and  the  same  remark  applies  to  asphyxiation 
in  atmospheres  containing  a  low  percentage  of  oxygen  in  mines, 
wells,  etc.  In  CO  poisoning,  as  will  be  explained  in  Chapter  VII, 
there  is  not  so  much  danger  from  this  cause,  so  that  extreme  anox- 
aemia may  exist  for  a  long  time  without  death  occurring. 

After  the  respiratory  center  has  been  over-fatigued  in  conse- 
quence of  anoxaemia,  the  effects  may  not  pass  off  for  a  very  long 
period.  The  breathing  on  exertion,  or  even  during  rest,  is  ab- 
normally shallow ;  and  the  peculiar  group  of  symptoms  observed 
in  the  neurasthenic  condition  so  familiar  during  the  war,  and  al- 
ready referred'  to  in  Chapter  III,  is  observed.  This  condition  may 


RESPIRATION  131 

remain  for  months  after  severe  anoxaemia,  and  is  often  mistaken 
for  organic  heart  injury. 

In  considering  the  effects  of  anoxaemia  a  factor  comes  in  which 
must  always  be  borne  in  mind — namely  that  of  adaptation  or  ac- 
climatization. This  may  act  in  two  different  ways.  In  the  first 
place  adaptation  may  bring  it  about  that  the  anoxaemia  which 
would,  without  adaptation,  exist  is  greatly  diminished.  This  form 
of  adaptation  is  very  clearly  seen  in  persons  living  at  great  alti- 
tudes, and  will  be  discussed  in  detail  in  later  chapters.  In  the 
second  place  the  tissues  may  adapt  themselves  to  a  lower  partial 
pressure  of  oxygen.  About  this  second  form  of  adaptation  our 
knowledge  is  at  present  very  imperfect;  but  it  seems  to  me 
that  clinical  evidence  points  strongly  to  its  existence.  Perhaps  the 
clearest  evidence  is  afforded  by  cases  of  congenital  heart  defect, 
in  which  part  of  the  venous  blood  passes  direct  to  the  left  side  of 
the  heart  without  first  passing  through  the  lungs.  In  these  cases 
of  "Morbus  coeruleus"  the  arterial  blood  is  always  more  or  less 
blue,  and  becomes  extremely  blue  on  muscular  exertion,  so  that 
one  can  always  recognize  this  condition  in  persons  walking  in  the 
street.  The  remarkable  point,  however,  is  that  in  spite  of  the  an- 
oxaemic  condition  of  the  arterial  blood  these  persons  may  get  on 
quite  well,  and  be  able  to  walk  at  a  good  pace.  On  account  of  the 
large  increase  in  their  haemoglobin  percentage,  they  have  plenty 
of  oxygen  in  their  blood,  but  at  a  low  partial  pressure.  It  seems 
hardly  possible  to  doubt,  therefore,  that  their  tissues  have  become 
adapted  to  the  low  partial  pressure  of  oxygen;  and  the  same 
adaptation  probably  exists  to  a  considerable  extent  in  many 
chronic  cases  of  valvular  heart  disease,  emphysema,  etc. 

The  fact  that  cyanosis  may  exist  without  harm  in  chronic  cases 
of  disease  has  certainly  contributed  greatly  to  the  general  failure 
to  recognize  the  gravity  of  anoxaemia  in  persons  not  adapted. 
Adaptation  is  a  process  which  always  requires  time,  and  the  time 
factor  must,  therefore,  be  taken  into  account  in  judging  of  the 
physiological  effects  of  anoxaemia. 


CHAPTER  VII 
The  Causes  of  Anoxaemia. 

IN  the  previous  chapter  anoxaemia  has  been  defined  as  the  condi- 
tion in  which  the  partial  pressure  of  oxygen,  or,  what  comes  to 
practically  the  same  thing,  the  amount  of  free  oxygen,  in  the 
systemic  capillaries  generally,  is  abnormally  low.  The  causes  of 
this  condition  must  now  be  examined. 

The  first  and  most  important  cause  of  anoxaemia  is  defective 
saturation  of  the  arterial  haemoglobin  with  oxygen.  This  may,  as 
we  shall  see,  arise  from  several  causes ;  but  the  most  obvious  of 
these  is  defective  partial  pressure  of  oxygen  in  the  alveolar  air. 
It  will  be  shown  in  Chapter  IX  that  during  rest  under  normal 
conditions  oxygen  passes  into  the  blood  through  the  alveolar 
epithelium  by  a  process  of  simple  diffusion,  and  that  the  oxygen 
pressure  in  the  arterialized  blood  leaving  each  alveolus  is  exactly 
that  of  the  air  in  the  alveolus.  For  the  purposes  of  the  present 
discussion  we  may  provisionally  assume  that  this  is  always  the 
case  during  rest,  so  long  as  the  lungs  and  the  inspired  air  are 
normal,  although  modifications  in  this  assumption  must  be  intro- 
duced later. 

In  the  light  of  this  assumption  and  of  our  knowledge  of  the 
dissociation  curve  of  oxyhaemoglobin,  it  might  seem  at  first  that 
we  are  justified  in  assuming  that  the  oxygen  pressure  of  mixed 
arterial  blood  is  simply  that  of  mixed  alveolar  air  as  ordinarily 
obtained  for  analysis  by  the  methods  already  described.  In  favor 
of  this  assumption  is  the  now  well-ascertained  fact  that  the 
breathing  is  regulated  under  ordinary  conditions  in  close  ac- 
cordance with  the  pressure  of  CO2  in  the  mixed  alveolar  air,  as 
explained  in  Chapter  II.  Variations  in  average  alveolar  CO2  pres- 
sure are  thus  a  direct  measure  of  variations  in  the  CO2  pressure 
of  the  arterial  blood ;  and  it  was  natural  to  assume,  as  was  done 
by  myself  and  others  till  lately,  that  variations  in  alveolar  oxygen 
pressure  must  also  be  a  measure  of  variations  in  the  oxygen  pres- 
sure of  the  arterial  blood.  One  known  difficulty  in  this  assumption 
lay  in  the  fact  that  the  arterial  oxygen  pressure,  as  measured  in 
animals  by  the  aerotonometer  (Chapter  IX)  is  nearly  always 
lower,  and  sometimes  considerably  lower,  than  the  alveolar  oxy- 
gen pressure;  but  various  explanations  of  this  difficulty  had  been 
adopted  by  myself  and  others. 


RESPIRATION 


133 


A  new  and  important  light  was  thrown  on  the  whole  subject  in 
the  course  of  a  study  by  Meakins,  Priestley,  and  myself  of  the 
"neurasthenia"  produced  by  gassing  and  other  causes  during  the 
war.1  As  mentioned  in  Chapter  III,  the  breathing  in  these  patients 
is  abnormally  frequent  and  shallow,  particularly  on  exertion.  It 
was  also  found  that  addition  of  oxygen  to  their  inspired  air  was  of 
considerable  service  during  any  ordinary  exertion,  and  that  in 
some  of  them  the  lips  became  blue  on  exertion  unless  oxygen  was 
given.  As  there  was  no  sign  of  anything  seriously  abnormal  in 
their  lungs,  we  were  led  to  suspect  that  the  shallow  breathing  was 
somehow  causing  anoxaemia.  This  led  us  to  make  experiments 


Figure  43. 
"Concertina"  apparatus  for  continuous  record  of  respiration. 

on  the  effects  of  shallow  breathing  in  normal  persons,  and  for  this 
purpose  we  devised  the  apparatus2  shown  in  Figure  43.  The 
subject  inspires  through  the  mouthpiece  and  inspiratory  valve 
from  the  recording  "concertina."  The  bottom  of  this  moves  up- 
wards with  inspiration,  and  records  the  movement  by  means  of 
an  inked  pen  on  the  drum.  The  bottom  comes  down  on  a  movable 
stop,  and  by  moving  this  upwards  the  maximum  capacity  of  the 
concertina  can  be  reduced  to  whatever  is  desired.  During  expira- 
tion the  expired  air  passes  out  by  the  rubber  expiratory  valve. 
At  the  same  time  the  expiratory  pressure  is  communicated  to  a 

1  Haldane,  Meakins,  and  Priestley,  Journ.  of  Physiol.,  LII,  p.  433,  1919. 

2  Made  by  Messrs.  Siebe  Gorman  &  Co.,  187  Westminster  Bridge  Road,  London. 


RESPIRATION  135 

tambour  the  movement  of  which,  as  shown,  closes  a  circuit  from 
an  accumulator  or  from  the  lighting  circuit  through  a  rheostat. 
This  circuit  passes  through  an  electromagnet  which  instantly 
lifts  a  valve  and  admits  air  freely  into  the  concertina,  which  at 
once  refills  itself.  At  the  end  of  expiration  the  circuit  is  instantly 
broken  and  the  valve  closes,  so  that  only  the  volume  of  air 
contained  in  the  concertina  can  be  inspired  at  the  next  inspiration. 
In  this  way  the  amount  of  air  taken  in  per  breath  can  be  limited, 
and  a  continuous  record  is  at  the  same  time  obtained  of  the  depth 
and  frequency  of  respiration.  With  the  concertina  fully  open 
ordinary  records  of  the  breathing  are  obtained,  and  any  gaseous 
mixture  can  be  supplied  through  a  glass  cylinder  which  incloses 
the  electromagnet  and  valve.  The  advantage  of  this  method  is 
that  it  is  capable,  not  merely  of  permitting  a  study  of  shallow 
breathing,  but  also  of  giving  a  continuous  quantitative  record  of 
any  sort  of  breathing.  The  old  stethographic  method  of  recording 
the  breathing  is  apt  to  be  misleading,  since  it  does  not  give  a 
quantitative  record. 

When  the  depth  of  inspiration  is  limited  by  means  of  this  ap- 
paratus the  natural  impulse,  at  first,  is  to  continue  the  inspiratory 
effort  at  the  end  of  each  inspiration,  as  the  Hering-Breuer  reflex 
has  not  given  the  signal  for  expiration.  With  a  little  practice, 
however,  the  breathing  goes  quite  easily,  and  the  frequency  in- 
creases in  proportion  as  the  depth  is  diminished.  When  the  depth 
is  greatly  limited  the  breathing  becomes  very  frequent — 100  or 
more  a  minute. 

On  observing  the  breathing  when  the  depth  was  gradually  more 
and  more  limited,  we  found  that  the  breathing  became  periodic 
very  readily.  As  already  explained,  periodic  breathing  is  a  symp- 
tom of  anoxaemia,  and  this  fact  led  us  to  try  the  effect  of  adding 
a  little  oxygen  to  the  inspired  air.  This  promptly  abolished  the 
periodic  breathing,  as  shown  in  Figure  44.  There  could  thus  be 
no  doubt  that  the  periodic  breathing  was  due  to  imperfect  oxy- 
genation  of  the  arterial  blood.  In  some  persons,  such  as  myself, 
the  periodic  breathing  was  produced  much  more  readily,  and  in  a 
more  striking  degree,  than  in  other  persons.  This,  as  already 
mentioned  in  Chapter  VI,  is  due  to  individual  differences  in  the 
response  of  the  respiratory  center  to  anoxaemia. 

We  at  first  thought  that  the  anoxaemia  must  be  due  to  the  fresh 
air  not  penetrating  properly  to  the  deep  (air-sac)  alveoli  when 
the  breathing  was  shallow ;  but  on  examining  samples  of  the  deep 
alveolar  air  during  a  prolonged  experiment,  we  were  disappointed 


136 


RESPIRATION 


to  find  that  in  the  deepest  alveolar  air  the  oxygen  percentage,  so 
far  from  being  lower,  was  actually  higher  than  usual.  There  was 
thus  hyperpnoea  from  want  of  oxygen,  and  yet  the  deep  alveolar 
air  contained  more  oxygen  than  usual.  The  breathing  was,  how- 
ever, very  inefficient  and  therefore  greatly  increased  in  amount, 
as  the  dead  space  told  much  more  than  with  normal  breathing, 
so  that  the  percentage  of  CO2  in  the  expired  air  was  very  low. 

On  turning  the  matter  over,  we  bethought  ourselves  of  some 
anatomical  observations  collected  by  Professor  Arthur  Keith  in 
"Further  Advances  in  Physiology,"  edited  by  Professor  Leonard 
Hill,  1909.  He  showed  in  this  essay  that  during  inspiration  the 
lungs  do  not  expand  equally  and  simultaneously  at  all  parts, 
but  open  out  part  by  part,  somewhat  like  the  opening  of  a  lady's 
fan.  The  parts  nearest  the  moving  chest  walls  (for  instance  the 
diaphragm)  expand  first,  and  other  parts  follow.  It  follows  from 
this,  that  in  shallow  breathing  the  lungs  will  be  very  unevenly 
ventilated.  Only  certain  parts  will  expand  properly,  and  on  ac- 


6.6       6.0 


PRESSURE  OF  CO^ 
PERCENT  OF  AN  ATMOSPHERE 
S3      4.6      4.0      3.3      2.6 


20      /.3       0.7 


024 


68/0/2  14  16  Id  20~Z2  24  26  26  30  32  54  36  38  4042  44       3 
PERCENT  OF  AN  ATMOSPHERE  ^ 

OXYGEN  PRESSURE 

Figure  45. 
Dissociation  curves  of  blood  for  COa  and  oxygen. 

count  of  the  increased  frequency  of  breathing  they  will  receive 
much  more  than  their  proper  share  of  fresh  air,  while  the  other 
parts  which  do  not  expand  will  receive  much  less. 

The  consequence  of  this  will  be  that  the  venous  blood  passing 
through  the  unexpanded  parts  of  the  lungs  will  be  very  im- 
perfectly arterialized,  whereas  in  the  expanded  parts  the  blood 
will  be  more  arterialized  than  usual.  The  mixed  arterial  blood  will 
thus  be  a  mixture  of  over-arterialized  and  under-arterialized 


RESPIRATION 


137 


blood.  To  see  what  the  results  of  this  mixture  will  be,  we  must 
refer  to  the  respective  dissociation  curves  for  the  oxygen  and  the 
CO2  present  in  blood,  taking  also  into  account  the  action  of  oxygen 
in  expelling  CO2  from  venous  blood,  as  shown  on  the  curve  in 
Figure  26.  For  convenience'  sake  the  two  relevant  curves  are 
plotted  together  in  Figure  45,  taken  from  our  paper.  It  will  at 
once  be  seen  that  the  over-ventilation  in  some  parts  of  the  lungs 
will  wash  out  CO2  from  the  blood  in  the  same  proportion  as  the 
under-ventilation  fails  to  wash  it  out.  The  mixed  arterial  blood 
will  thus  be  normal  as  regards  its  content  of  CO2  if  the  total  al- 
veolar ventilation  is  normal.  On  the  other  hand,  the  over- ventila- 
tion will  hardly  increase  at  all  the  charge  of  oxygen  in  the  blood 
from  the  over- ventilated  alveoli,  since  this  blood  is  on  the  flat  part 
of  the  curve  with  the  alveolar  oxygen  pressure  at  perhaps  16  or 
1 8  per  cent  of  an  atmosphere.  The  under-ventilation,  on  the  other 
hand,  will  leave  the  venous  blood  nearly  venous  and  on  the  steep 
part  of  the  oxyhaemoglobin  curve,  with  a  large  deficiency  of  oxy- 
gen. The  mixed  arterial  blood  will,  therefore,  be  seriously  deficient 
in  oxygen,  and  symptoms  of  anoxaemia  will  consequently  be  pro- 
duced. As  one  of  these  symptoms  is  increase  in  the  breathing,  there 
will  be  some  compensation,  and  the  CO2  percentage  of  the  mixed 
alveolar  air  will  fall  somewhat,  there  being  a  corresponding  rise 
also  in  the  oxygen  percentage,  as  was  actually  found  in  our  ex- 
periments. 

There  is  thus  a  very  complete  explanation  of  our  experimental 
results,  and  also  of  the  symptoms  of  anoxaemia  in  the  neurasthenic 
cases ;  but  clearly  it  is  necessary  to  modify  radically  the  idea  that 
the  alveolar  oxygen  pressure  gives  the  oxygen  pressure  of  the 
mixed  arterial  blood.  We  have  no  guarantee  that  even  during 
quite  normal  breathing  the  distribution  of  air  in  the  individual 
lung  alveoli  corresponds  exactly  with  the  distribution  of  blood  to 
them.  Unless  this  correspondence  is  exact  some  alveoli  will  re- 
ceive more  air  in  proportion  to  their  blood  supply  than  others, 
and  as  a  consequence  the  mixed  arterial  blood  will  be  a  mixture 
of  more  and  less  fully  arterialized  blood,  with  some  of  the  con- 
sequences first  discussed.  It  is  probable  indeed  that  in  some  way 
or  other  the  air  supply  is  proportioned  to  the  blood  supply, 
whether  by  regulation  through  the  muscular  coats  of  the  bron- 
chioles or  regulation  of  the  blood  distribution ;  but  it  is  also  certain 
that  this  proportioning  is  only  an  approximation.  The  fact  that 
in  animals  the  aerotonometer  gives  a  lower  arterial  oxygen  pres- 
sure than  the  alveolar  oxygen  pressure  (Chapter  IX)  is  most 


I38  RESPIRATION 

naturally  explained  on  the  theory  that  the  proportioning  is  only 
approximate,  and  there  are  various  other  facts  which  point  in  the 
same  direction. 

One  of  these  facts  is  as  follows.  When  the  breathing  is  suddenly 
interrupted  voluntarily  the  breath  can  be  held  for  a  certain  time — 
usually  about  40  seconds  if  only  an  ordinary  breath  is  inspired 
before  the  interruption.  Leonard  Hill  and  Flack3  discovered,  how- 
ever, that  if  the  lungs  are  filled  with  oxygen  first  the  breath  can 
be  held  for  two  or  three  times  longer ;  also  that  the  alveolar  CO2 
percentage  is  considerably  higher  at  the  breaking  point.  On  the 
other  hand,  when  the  same  air  was  rebreathed  continuously  from 
a  small  bag  filled  at  the  start  with  a  breath  of  alveolar  air,  the 
alveolar  CO2  percentage  went  as  high  as  when  the  breath  was 
held  with  oxygen,  though  not  so  high  as  when  oxygen  was  re- 
breathed  from  the  bag.  The  following  table,  illustrating  these 
results,  is  taken  from  Hill  and  Flack's  paper. 

It  was  difficult,  at  the  time,  to  interpret  these  results  satisfac- 
torily, since  the  alveolar  oxygen  percentages,  when  the  breath  was 
held  after  breathing  ordinary  air,  did  not  seem  to  be  low  enough  to 
stimulate  the  breathing  appreciably.  In  order  to  obtain  still  more 
definite  information  Douglas  and  I  repeated  the  observations, 
but  in  such  a  way  as  to  have  great  variations  in  the  alveolar  oxy- 
gen percentage.4  We  then  found  that  the  beneficial  effects  of  in- 
creasing the  alveolar  oxygen  percentage  were  still  evident,  though 
to  a  diminishing  extent,  till  1 7  per  cent  of  oxygen  was  present  in 
the  alveolar  air.  Oxygen  in  excess  of  this  made  no  difference.  But 
1 7  per  cent  is  3  per  cent  more  than  what  is  present  in  normal  al- 
veolar air;  and,  as  we  have  already  seen,  there  are  no  effects  on 
the  breathing  from  want  of  oxygen  when  ordinary  air  is  breathed 
by  normal  persons,  or  even  when  the  oxygen  percentage  of  the 
alveolar  runs  down  to  10  or  even  8  per  cent.  The  results  were 
therefore  very  mysterious  at  the  time,  and  we  were  compelled  to 
adopt  the  improbable  hypothesis  that  holding  the  breath  has  some 
considerable  effect  on  the  circulation  in  the  brain,  leading  to 
anoxaemia  of  the  respiratory  center.  There  is,  however,  no  reason 
whatever  to  expect  such  an  effect. 

The  experiments  on  shallow  breathing  have  furnished  the 
solution  to  this  mystery.  It  is  evident  that  the  relation  between 
blood  supply  and  ventilation  in  individual  groups  of  alveoli  is 
not  an  even  one.  In  some  alveoli  the  oxygen  runs  down  and  CO2 

'Leonard  Hill  and  Flack,  Journ.  of  Physiol.,  XXXVII,  p.  77,  1908. 
4  Douglas  and  Haldane,  Journ.  of  Physiol.,  XXXVIII,  p.  425,  1909. 


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RESPIRATION 


accumulates  faster  than  in  others.  Hence  in  some  the  blood  is 
less  perfectly  oxygenated;  and  if  the  breath  is  held  for  a  time 
this  imperfect  oxygenation  becomes  more  and  more  marked  till 
at  last  the  mixed  arterial  blood  is  very  considerably  short  of  oxy- 
gen, just  as  when  the  breathing  is  very  shallow.  Hence  the  oxygen 
percentage  of  the  mixed  alveolar  air  becomes  altogether  deceptive 
as  an  index  of  the  degree  of  oxygenation  of  the  mixed  arterial 
blood,  although  the  CO2  percentage  remains,  for  the  reasons  al- 
ready given,  a  reliable  index  of  the  degree  of  saturation  of  arterial 
blood  with  CO2.  The  results  of  these  experiments  on  holding  the 
breath  are  thus  very  valuable  as  furnishing  evidence  that,  even 
with  normal  or  increased  inspirations,  the  relation  between  blood 
supply  and  air  supply  varies  considerably  in  different  alveoli. 

That  the  arterial  blood  does  actually  become  imperfectly  oxy- 
genated when  the  breath  is  held  has  been  quite  recently  demon- 
strated by  Meakins  and  Davies.5  They  found  that  on  holding  a 
deep  breath  of  air  for  40  seconds,  the  haemoglobin  of  the  arterial 


-?r 

r 

* 

o 

€ 

>* 

©~^ 

0 

%H 

u 

3 

1 

& 

•a  30 

20    40     60    80    100    120  M 

0  '6O   180  200  220  240  260  280  300  320  540  36O  380  400  420  440 
PRESSURE  OF  OziN  MM.H<J. 

Figure  46. 
Alveolar  CO2  during  breath  holding  after  inhalation  of  oxygen. 

blood  drawn  from  the  radial  artery  was  only  83.8  per  cent  satu- 
rated with  oxygen,  although  the  mixed  alveolar  air  contained 
13.4  per  cent  of  oxygen.  Had  air  of  this  composition  been  dis- 
tributed evenly  throughout  the  alveoli  the  haemoglobin  would 
have  been  97  per  cent  saturated  with  oxygen. 

A  further  series  of  experiments  which  Douglas  and  I  performed 
is  very  instructive  in  this  connection.  As  already  mentioned  in 
Chapter  V,  the  alveolar  CO2  percentage  rises  high  above  its 
normal  value  before  the  end  of  an  apnoea  after  forced  breathing 
with  extra  oxygen.  We  observed  how  high  the  alveolar  CO2  pres- 
sure went  when  there  were  varying  pressures  of  oxygen  in  the 

'Meakins  and  Davies,  Journ.  of  Pathol.  and,  Bacter.,  XXIII,  p.  451,1920. 


RESPIRATION  I4I 

mixed  alveolar  air  at  the  end  of  the  apnoea  produced  by  two 
minutes  of  forced  breathing,  and  the  results  are  plotted  in  Figure 
46.6  It  will  be  seen  that  the  CO2  pressure  (and  of  course  also  the 
length  of  the  apnoea)  rises  with  the  alveolar  oxygen  pressure 
until  the  latter  reaches  about  120  mm.  (corresponding  to  about 
17  per  cent  of  oxygen  in  the  dry  alveolar  air),  beyond  which  a 
further  rise  in  alveolar  oxygen  pressure  has  no  effect.  In  this  case 
the  oxygen  pressure  in  all  the  lung  alveoli  would  be  at  a  more  or 
less  equal  high  level  at  the  beginning  of  an  apnoea,  but  would 
fall  at  unequal  rates  in  the  different  alveoli.  Accordingly  at  the 
end  of  apnoea  the  mixed  arterial  blood  would'  be  getting  venous 
unless  the  average  alveolar  air  contained  more  than  17  per  cent 
of  oxygen.  And  yet  as  little  as  8  per  cent  would  be  enough  to 
prevent  this  effect  if  the  air  was  evenly  distributed  in  relation  to 
the  blood  supply  of  the  alveoli,  or  if  respiratory  movements  pre- 
vented anything  more  than  comparatively  slight  variations  in 
the  oxygen  percentages  in  different  alveoli. 

Judging  from  aerotonometer  experiments  on  normal  animals, 
and  from  direct  determinations  on  human  arterial  blood,  the  hae- 
moglobin of  average  human  arterial  blood  is  only  about  94  to  96 
per  cent  saturated  with  oxygen — about  2  per  cent  less  than  if  the 
whole  arterial  blood  was  saturated  to  the  oxygen  pressure  of  the 
mixed  alveolar  air.  A  very  accurate  series  of  determinations 
described  by  Meakins  and  Davies  in  the  paper  just  quoted  showed 
that  in  different  healthy  persons  the  saturation  varies  from  94  to 
96  per  cent.  The  slight  variations  seem  to  be  due  to  the  variations 
which  Barcroft  described  in  the  oxyhaemoglobin  dissociation 
curves  of  different  individuals. 

The  periodic  breathing  produced  by  shallow  breathing  differs 
strikingly  from  the  periodic  breathing  produced  by  anoxaemia 
in  normal  persons.  As  will  be  seen  from  Figure  44,  the  periods 
are  much  longer,  and  in  this  respect  bear  a  striking  resemblance 
to  ordinary  clinical  Cheyne-Stokes  breathing.  The  reason  why 
the  periods  are  longer  is  evident  enough :  for  the  shallow  breath- 
ing is  very  ineffective  in  raising  the  oxygen  percentage  in  the 
badly  ventilated  parts  of  the  lungs  and  so  relieving  the  anox- 
aemia. The  relief  thus  comes  slowly.  The  breathing,  therefore, 
"waxes  and  wanes"  gradually,  as  in  clinical  Cheyne-Stokes 
breathing.  In  hibernating  animals  similar  breathing  is  often  ob- 
served and  can  be  explained  in  the  same  way,  as,  owing  to  the 
small  production  of  CO2,  the  breathing  is  very  shallow. 

9  Douglas  and  Haldane,  Journ.  of  Physiol.,  XXXVIII,  p.  401,   1909. 


I42  RESPIRATION 

Ordinary  clinical  Cheyne- Stokes  breathing  is  evidently  a  symp- 
tom of  anoxaemia  due  often  to  the  shallow  breathing  which  char- 
acterizes a  failing  respiratory  center.  This  failure  may  be  that  of 
approaching  death,  since  the  anoxaemia  itself  tends  to  hasten  the 
failure  of  the  center,  as  already  explained  in  Chapter  VI.  There 
is  thus  a  vicious  circle  which,  unless  broken  in  some  way,  must  end 
in  death  from  anoxaemia,  just  as  in  the  case  of  an  airman  at  a 
dangerously  high  altitude.  The  color  of  the  lips,  in  conjunction 
with  the  diminishing  depth  of  the  breathing,  points  clearly  to 
what  is  happening. 

It  is  now  evident  that  the  anoxaemia  so  often  present  in  disease, 
but  so  seldom  recognized  as  such,  is  due  in  a  large  number  of 
cases  to  the  shallow  breathing  characteristic  of  a  damaged  or 
"fatigued"  respiratory  center,  whatever  the  original  cause  of  the 
damage  or  fatigue  may  be.  It  is  also  evident  that  frequency  of 
breathing  has  assumed  a  significance  which  it  did  not  previously 
possess,  since  frequency  is  very  often  an  index  of  shallowness  of 
breathing,  damage  to  the  respiratory  center,  and  consequently 
impending  danger  from  anoxaemia.  The  frequent  and  shallow 
breathing  in  surgical  shock,  or  in  various  forms  of  influenza  and 
pneumonic  conditions,  or  as  it  may  occur  in  many  other  forms  of 
disease,  is  a  symptom  of  which  the  possible  deadly  import  will  be 
evident  enough  to  those  who  have  read  the  preceding  chapter  in 
connection  with  what  has  just  been  said.  In  this  connection  I 
should  like  also  to  emphasize  the  fact  that,  as  fully  explained  in 
the  last  chapter,  it  is  unsafe  to  judge  of  the  degree  of  anoxaemia 
by  the  degree  of  cyanosis.  The  anoxaemia  is,  and  must  be,  ac- 
companied by  alkalosis,  so  that  the  oxyhaemoglobin  holds  on  more 
tightly  to  its  oxygen,  and  this  alkalosis  may  become  extreme  with 
very  shallow  and  rapid  breathing. 

Chronic  fatigue  or  failure  of  the  respiratory  center  is  seen  in 
neurasthenia  and  various  other  forms  of  disease;  but  failure  of 
the  respiratory  center  may  also  occur  in  acute  and  sudden  attacks, 
which  are  often  associated,  either  primarily  or  secondarily,  with 
anginal  pain.  The  patient  may  feel  that  he  cannot  expand  his 
chest  to  breathe,  just  as  if  it  were  mechanically  constricted;  and 
he  rapidly  develops  asphyxial  symptoms,  with  very  frequent  and 
shallow  breathing.  In  reality,  apparently,  he  is  in  the  grip  of  the 
Hering-Breuer  reflex,  which,  as  explained  in  Chapter  III,  assumes 
exaggerated  influence,  owing  to  the  failure  of  the  respiratory 
center.  These  attacks,  though  they  usually  pass  off,  are  sometimes 
very  dangerous;  and  many  sudden  deaths  appear  to  be  due  to 


RESPIRATION 


143 


them.  They  are  specially  liable  to  occur  at  night.  The  rapid 
breathing  is  apt  to  produce  the  impression  in  a  physician  that  it  is 
the  heart  and  not  the  breathing,  that  has  failed ;  and  this  impres- 
sion may  be  apparently  confirmed  by  the  presence  of  secondary 
anginal  pain.  In  all  doubtful  cases,  the  effects  of  properly  admin- 
istering oxygen  will  decide  the  diagnosis.  If  the  immediate  cause 
of  the  symptoms  is  failure  of  the  respiratory  center,  the  effects 
of  the  oxygen  are  rapid  and  prompt,  and  have  been  so  in  cases 
which  have  chanced  to  come  under  my  own  observation. 

It  is  evident  that  anoxaemia  caused  by  irregular  distribution 
of  oxygen  among  the  lung  alveoli  may  be  due  to  a  variety  of 
causes.  One  of  these  is  emphysema ;  for  the  emphysematous  parts 
of  a  lung  will  naturally  be  supplied  with  far  more  than  the  proper 
proportion  of  air  to  suit  their  greatly  diminished  respiratory 
surface,  while  the  other  parts  will  receive  correspondingly  less 
air.  The  arterial  blood  will  thus  be  a  mixture  of  over-arterialized 
I  2 


llllllllllltllllllllllllllllllllllllllM 


Figure  47. 

Subject  J.  S.  H.  Rebreathing  in  and  out  of  50  liter  cylinder.  Time  marker  = 
2  seconds,  i.  Sitting.  2,  Lying. 

and  under-arterialized  blood,  with  resulting  anoxaemia,  which 
may  or  may  not  be  compensated  by  one  or  other  of  the  processes 
to  be  described  in  succeeding  chapters. 

Another  cause  of  the  same  general  character  is  bronchitis  or 
asthma.  The  irregular  partial  blocking  or  muscular  constriction 
of  the  bronchi  and  bronchioles  in  these  conditions  must  lead  to 


144 


RESPIRATION 


irregular  distribution  of  fresh  air  to  the  alveoli,  even  though  the 
average  distribution,  as  shown  by  the  volume  of  air  breathed,  is 
greatly  increased.  Hence  the  mixed  arterial  blood  will  be  deficient 
in  oxygen,  and  grave  anoxaemia  may  develop.  Here,  also,  the 
effects  of  oxygen  administration  will  decide  the  diagnosis  of  the 
condition. 

We  found  that  the  recumbent  position  greatly  favors  the  de- 
velopment of  periodic  breathing,  and  therefore  of  anoxaemia. 
We  also  found  that  when  a  normal  person  assumes  the  recumbent 
position,  the  usual  result  is  that  the  breathing  becomes  slower  and 
deeper.  In  my  own  case,  for  instance,  the  frequency  diminishes 
from  about  15  in  the  sitting  or  upright  position  to  7  or  8,  while 
the  depth  correspondingly  increases,  so  as  to  keep  the  alveolar 
CO2  pressure  nearly  the  same  (see  Figure  47).  The  cause  of  this 
phenomenon  is  not  altogether  clear,  but  is  probably  the  increased 
resistance  thrown  on  the  diaphragm  in  the  recumbent  position, 
as  the  weight  of  the  liver  and  other  abdominal  organs  assists  the 
descent  of  the  diaphragm  in  the  upright  position.  Rontgen  ray 


Figure  48. 

Subject  J.  G.  P.  i.  Breathing  restricted  by  concertina — lying.  2.  Breathing 
restricted  to  same  extent — sitting.  3.  Breathing  further  restricted — sitting.  Oxy- 
gen given.  Curves  read  left  to  right.  Inspiration  upstroke.  Time  marker  = 
seconds. 

photographs  which  we  took  to  show  the  position  of  the  diaphragm 
favored  this  explanation ;  and,  assuming  it  to  be  correct,  the  effect 
of  the  recumbent  position  may  well  be  similar  to  the  slowing 
effect  produced  by  resistance  as  shown  in  Chapter  III.  Whatever 


RESPIRATION 


145 


the  cause  of  the  natural  increased  depth  may  be,  it  is  evident  that 
in  the  recumbent  position  the  tendency  to  irregular  distribution 
of  fresh  air  in  the  lung  alveoli  with  any  given  depth  of  breathing 
is  much  increased,  so  that  anoxaemia  from  this  cause,  as  shown 
in  normal  persons  by  periodic  breathing,  is  much  more  readily 
produced.  In  my  own  case  periodic  breathing  is  rapidly  produced 
in  the  recumbent  position  when  the  breathing  is  kept  at  over  20 
per  minute  by  artificially  limiting  the  depth  by  means  of  our 
apparatus,  whereas  in  the  upright  position  there  is  no  such  effect. 
The  effect  of  the  recumbent  position  is  shown  in  Figure  48. 

We  have  thus  a  simple  explanation  of  a  phenomenon  which 
has  been  familiar  to  physicians  since  early  times,  but  which  has 
hitherto  never  been  satisfactorily  explained.  When  patients  are 


42 

41 
40 
39 


10 


fc  37 
|  36 

!» 

I  34 
1.33 
3*32 

V. 

I  31 
*30 

29 

28 

800         700          600          500          400 
Barometric  Pressure  m  mm  of  mercury 

Figure  49. 

Effects  of  diminished  barometric  pressure  on  the 
alveolar  gas-pressures.  The  thick  lines  show  the 
alveolar  CC>2  pressure,  and  the  thin  lines  the  alveolar 
O2  pressure.  The  dotted  lines  refer  to  the  experiment 
in  which  oxygen  was  added  to  the  air. 

short  of  breath  during  illness  they  are  often  very  uncomfortable 
in  the  recumbent  position,  and  may  become  dangerously  worse 
if  not  propped  up  in  bed  or  in  a  chair.  This  condition  is  known  as 


30Q 


I46  RESPIRATION 

orthopnoea,  and  its  causation  now  seems  evident.  With  a  failing 
respiratory  center,  and  consequent  abnormal  shallowness  of  respi- 
ration, anoxaemia  is  the  natural  result  of  the  recumbent  position; 
and  the  prevention  of  this  anoxaemia  by  keeping  the  patient  in  a 
sitting  position  becomes  an  important  part  of  treatment  unless 
the  same  object  is  attained  by  oxygen  administration. 

Defective  distribution  of  air  in  the  lung  alveoli  is,  of  course, 
only  one  of  the  causes  of  defective  oxygenation  of  the  arterial 
blood;  but  I  have  dealt  with  this  cause  first,  not  only  because  it 
is  of  very  great  importance  in  medicine,  but  because  an  under- 
standing of  it  is  essential  to  the  understanding  of  other  causes  of 
defective  oxygenation. 

A  second  and  hitherto  much  better  known  cause  of  defective 
oxygenation  of  the  arterial  blood  is  a  deficiency  in  the  partial 
pressure  of  oxygen  in  the  inspired  air,  and  consequent  fall  in  the 
alveolar  oxygen  pressure.  As  shown  in  Chapter  II,  it  usually  re- 
quires a  fall  in  oxygen  percentage  from  the  normal  of  20.9  to 
about  14  per  cent,  or  a  third,  before  any  evident  effect  on  the 
breathing  is  produced  at  the  time  by  the  oxygen  deficiency.  Simi- 
larly a  fall  of  about  a  third  in  barometric  pressure  (corresponding 
to  about  1 1,500  feet  above  sea  level)  is  required.  Figure  49,  from 
a  paper  by  Boycott  and  myself,7  shows  that  until  the  barometric 
pressure  in  a  steel  chamber  falls  by  about  a  third,  the  normal 
alveolar  CO2  pressure  is  very  little  disturbed.  The  alveolar  CO2 
percentage  simply  goes  up  as  the  barometric  pressure  goes  down, 
but  the  pressure  of  CO2  remains  almost  the  same  in  the  alveolar 
air.  In  the  same  investigation  we  found  that  even  when  the  bar- 
ometric pressure  was  reduced  to  300  mm.  the  alveolar  CO2  pres- 
sure remained  the  same,  provided  that  any  excessive  fall  in  the 
oxygen  pressure  of  the  inspired  air  was  prevented  by  adding  oxy- 
gen to  the  air  of  the  chamber.  There  is  thus  no  trace  of  foundation 
for  Mosso's  contention8  that  the  diminished  mechanical  pressure 
of  the  air  produces  by  itself  a  diminished  saturation  of  the  blood 
with  CO2. 

Since  the  alveolar  air,  with  the  breathing  normal,  contains  about 
a  third  less  oxygen  than  the  inspired  air,  it  follows  that  when  the 
oxygen  percentage  or  partial  pressure  in  the  inspired  air  is  reduced 
by  a  third  the  alveolar  oxygen  percentage  will  be  reduced  to  about 
half — i.e.,  from  about  13  per  cent  of  an  atmosphere  to  about  6.5 
per  cent.  On  comparing  this  with  the  dissociation  curve  of  oxy- 

T  Boycott  and  Haldane,  Journ.  of  Physiol.,  XXXVII,  p.  355,  1908. 
8  Mosso,  Life  of  Man  on  the  High  Alps,  London,  p.  287,  1898. 


RESPIRATION 


147 


haemoglobin  it  will  be  seen  that  such  a  diminution  corresponds 
to  a  saturation  of  about  80  per  cent  of  the  haemoglobin  with  oxy- 
gen, and  that  any  further  diminution  will  cause  a  rapid  fall  in  the 
saturation.  The  air  produces  at  the  time  no  noticeable  discomfort, 
and  the  breathing  is  not  sensibly  affected,  although  the  lips  are 
slightly  bluish.  The  natural  conclusion  is  that  a  diminution  of 
about  15  per  cent  in  the  saturation  of  the  haemoglobin,  or  a  dimi- 
nution to  half  in  the  arterial  oxygen  pressure,  is  of  no  physio- 
logical importance,  even  though  the  lips  are  rather  dull  in  color. 
This  wholly  mistaken  idea  is,  however,  rudely  shaken  by  the 
effects  of  remaining  for  a  sufficient  time  in  the  atmosphere :  for 
the  observer  will  be  almost  certainly  prostrated  by  an  attack  of 
mountain  sickness  which  he  is  never  likely  to  forget  afterwards. 

If,  now,  in  order  to  escape  mountain  sickness,  the  pressure  of 
oxygen  in  the  inspired  air  is  only  diminished  by  one-seventh  (cor- 
responding to  a  height  of  4,500  feet;  or  an  oxygen  percentage  of 
17  at  ordinary  atmospheric  pressure),  there  will  be  no  appreciable 
blueness,  and  the  corresponding  saturation  on  the  oxyhaemoglobin 
dissociation  curve  will  be  only  3.5  per  cent  below  that  for  normal 
alveolar  air.  Nevertheless  there  will,  if  sufficient  time  is  given,  be 
quite  appreciable  physiological  responses,  which  will  be  discussed 
in  succeeding  chapters.  The  truth  is  that  in  the  long  run  the  body 
responds  in  a  fairly  delicate  manner  to  quite  small  diminutions 
in  the  oxygen  pressure  of  the  inspired  air. 

Let  us  now  look  at  the  matter  in  the  light  of  the  new  knowledge 
as  to  the  somewhat  imperfect  manner  in  which  air  is  distributed 
in  the  alveoli.  In  the  course  of  our  investigation  on  military 
neurasthenia,  we  placed  several  of  the  patients  in  a  steel  chamber 
and  observed  the  effects  of  diminished  pressure.  A  very  slight  dim- 
inution, corresponding  to  only  about  5,000  feet,  was  sufficient  to 
produce  in  them  urgent  respiratory  and  other  symptoms,  although 
they  were  doing  no  work.  Even  in  normal  persons  the  dissociation 
curve  of  oxyhaemoglobin  and  composition  of  the  mixed  alveolar 
air  are,  as  was  shown  above,  no  certain  guides  to  the  percentage 
saturation  of  the  haemoglobin,  or  oxygen  pressure  in  the  mixed 
arterial  blood.  As  a  matter  of  fact  the  blueness  of  the  lips  seen  in 
persons  freshly  exposed  to  very  low  atmospheric  pressure  seems 
to  be  often  much  greater  than  would  correspond  to  the  oxygen 
pressure  in  their  alveolar  air  when  due  allowance  is  made  for  the 
Bohr  effect  of  lowered  alveolar  CO2  pressure.  We  may  thus  be 
quite  sure  that  at  diminished  atmospheric  pressure  the  saturation 


148  RESPIRATION 

of  the  mixed  arterial  blood  with  oxygen  is  or  may  be  distinctly 
lower  than  corresponds  to  the  oxygen  pressure  of  the  alveolar  air. 

Poulton  and  I  found  that  when  a  small  quantity  of  air — about 
6  liters — was  rebreathed  continuously  up  to  the  verge  of  loss  of 
consciousness,  the  CO2  being  completely  absorbed  by  soda  lime, 
the  inspired  air  contained  only  4.8  per  cent  of  oxygen,  and  the 
alveolar  air  3.7  per  cent.  There  was  very  great  hyperpnoea;  for 
the  preformed  CO2  had  not  had  time  to  escape  in  the  manner 
already  referred  to  in  Chapter  VI.  The  respiratory  quotient  of 
the  alveolar  air  was  as  high  as  2.8.  The  experiment  was  then 
repeated  with  a  large  volume  of  air,  and  under  such  conditions 
that  the  oxygen  percentage  only  fell  very  slowly.  The  lowest  per- 
centage of  oxygen  that  could  now  be  reached  in  the  inspired  air 
without  great  confusion  of  mind  was  about  9.4,  with  about  4.6 
per  cent  (or  33  mm.)  in  the  alveolar  air.  There  was  no  noticeable 
hyperpnoea,  and  the  respiratory  quotient  was  normal.  The  al- 
veolar CO2  percentage  was  only  reduced  from  the  normal  of  5.7 
per  cent  to  4.6,  indicating  that  the  alveolar  ventilation  was  only 
increased  by  about  a  fourth. 

From  these  experiments  we  may  conclude  that  air  containing 
less  than  9.5  per  cent  of  oxygen  would  ordinarily  cause  disable- 
ment within  half  an  hour.  At  a  barometric  pressure  of  368  mm.,  or 
a  little  less  than  half  an  atmosphere,  corresponding  to  about 
20,500  feet  above  sea  level,  there  would  be  a  corresponding  drop 
in  the  alveolar  oxygen  pressure;  but  judging  from  my  own  ob- 
servations the  physiological  effects  are  very  distinctly  less  severe. 
This  is  probably  due  to  the  fact  that  in  rarefied  air  the  diffusion  of 
oxygen  within  the  lung  alveoli  is  much  more  free  than  at  atmos- 
pheric pressure.9  As  a  rule  no  very  serious  symptoms  are  ex- 
perienced at  the  time  till  the  barometric  pressure  has  fallen  to 
about  350  mm.  (corresponding  to  21,500  feet)  ;  but  in  this  respect 
different  individuals  vary  considerably.  It  must  also  be  borne  in 
mind  that  nervous  symptoms  of  anoxaemia  begin  to  appear  at 
altitudes  not  nearly  so  great.  At  320  mm.  (about  24,000  feet) 
most  persons,  including  myself,  are  soon  very  seriously  affected 
in  the  manner  described  in  Chapter  VI,  unless  they  are  acclima- 
tized. 

Another  cause  of  imperfect  oxygenation  of  the  arterial  blood 
is  that  there  may  not  be  sufficient  time  for  the  required  quantity 
of  oxygen  to  pass  into  the  blood  through  the  alveolar  epithelium. 
This  cause  of  anoxaemia  came  into  prominence  in  connection  with 

*  Haldane,  Kellas,  and  Kennaway,  Journ.  of  Physiol.,  LIU,  p.  195,  1915. 


RESPIRATION 


149 


the  effects  of  lung-irritant  poison  gas  during  the  war.  It  was  evi- 
dent from  the  first  cases  which  I  saw  in  April,  1915,  that  there  was 
acute  anoxaemia  due  to  imperfect  oxygenation  of  the  arterial 
blood.  There  were  the  ordinary  chlorine  symptoms  of  acute  bron- 
chitis, alveolar  inflammation,  and  oedema  of  the  lungs.  The  faces 
of  the  patients  were  deeply  cyanosed,  in  spite  of  considerably  in- 
creased breathing  of  adequate  depth.  At  first  it  was  suspected  that 
the  cyanosis  was  due  to  "toxaemia,"  causing  the  formation  in  the 
blood  of  methaemoglobin  or  some  similar  dark-colored  decompo- 
sition product;  but  on  diluting  a  drop  of  the  blood,  saturating 
with  CO,  and  comparing  the  solution  with  the  tint  of  similarly 
treated  normal  blood,  I  found  that  there  was  no  abnormal  pigment 
present,  so  that  the  blue  color  was  due  simply  to  anoxaemia.  That 
this  anoxaemia  was,  in  the  main  at  least,  due  to  delay  in  the  pas- 
sage of  oxygen  into  the  arterial  blood  was  then  confirmed  by  the 
fact  that  on  administering  oxygen  the  blue  color  changed  to  red, 
and  the  patients  improved  in  other  respects.  It  was  evident  that 
with  the  greatly  increased  partial  pressure  of  oxygen  in  the  al- 
veolar air,  the  oxygen  was  able  to  pass  into  the  blood  at  a  sufficient 
rate  to  saturate  or  nearly  saturate  the  blood,  and  thus  maintain 
life.  The  delayed  passage  was  probably  due  mainly  to  the  fact 
that  the  alveolar  walls  were  swollen  and  oedematous,  so  that  they 
did  not  allow  oxygen  to  pass  inwards  at  a  normal  rate.  As  will  be 
pointed  out  in  Chapter  IX,  this  condition  was  produced  experi- 
mentally in  animals  by  Lorrain  Smith.  The  distribution  of  air  in 
the  lung  alveoli  was  doubtless  also  gravely  interfered  with  by  the 
bronchitis  and  emphysema  caused  by  the  actions  of  chlorine, 
though  at  the  time  I  was  ignorant  of  the  importance  of  this  cause. 
To  judge  by  the  increased  breathing  there  was  also  much  dis- 
turbance in  the  excretion  of  CO2  by  the  lungs;  and  the  great  dis- 
tention  of  the  veins  and  other  signs  in  the  chlorine  cases  pointed 
in  this  direction  also. 

In  the  cases  of  poisoning  by  phosgene  and  other  lung  irritants 
used  later,  the  symptoms  of  irritation  of  the  air  passages  were 
much  less  prominent.  The  general  symptoms  corresponded  more 
closely  with  those  of  pure  anoxaemia.  This  was  particularly  true 
in  the  earlier  seen,  or  less  severe,  cases,  when  there  was  no  evi- 
dent oedema  of  the  lungs.  Thus,  at  first,  the  symptoms  of  acute 
anoxaemia  were  shown  only  on  muscular  exertion  sufficient  to 
cause  a  greatly  increased  need  for  oxygen ;  and  some  of  the  men 
who  were  apparently  at  the  time  only  slightly  affected  lost  con- 
sciousness or  died  as  a  result  of  muscular  exertion.  Others  suf- 


150  RESPIRATION 

fered  only  from  general  malaise  or  symptoms  similar  to  those  of 
mountain  sickness,  and  apparently  due  to  slight  anoxaemia.  In 
the  graver  cases  the  anoxaemia  was  usually  unaccompanied  by 
distention  of  the  lips  and  veins  with  blood,  and  the  cyanosis  was 
thus  of  the  leaden  or  gray  type,  just  as  in  cases  of  slowly  advancing 
anoxaemia  from  other  causes.  In  death  from  gradual  CO  poison- 
ing, for  instance,  there  is  no  extra  distention  of  the  lips  or  veins 
with  blood,  although,  of  course,  the  lips  are  not  gray  but  light 
pink.  Death,  in  the  phosgene  cases  and  probably  in  others,  seems 
to  have  been  finally  due  to  failure  of  the  respiratory  center,  the 
breathing  becoming  more  and  more  shallow  till  the  resulting 
increase  in  the  anoxaemia  ended  in  death.  Orthopnoea  was  a  very 
common  symptom  so  long  as  the  men  were  conscious. 

In  favorable  cases  of  ordinary  croupous  pneumonia  the  lips 
remain  of  a  good  color,  and  there  are  no  evident  signs  of  anoxae- 
mia ;  but  the  breathing  is  rapid,  and  correspondingly  shallow. 
The  danger  of  anoxaemia  is  therefore  not  far  off.  At  Cripple 
Creek  (at  an  altitude  of  about  10,000  feet)  I  was  told  that  cases  of 
commencing  pneumonia  were  at  once  put  on  the  train  and  sent 
down  to  the  prairie  level,  as  it  had  been  found  that  they  had  a 
very  poor  chance  if  treated  locally.  This  indicates  the  danger 
from  anoxaemia,  and  led  us,  in  the  Report  of  the  Pike's  Peak 
Expedition,  to  advocate  the  use  of  chambers  containing  air  en- 
riched with  oxygen  for  treating  pneumonia.  The  fact  that  there 
is  often  no  cyanosis  in  spite  of  very  extensive  lung  consolidation 
seems  to  show  that  the  pulmonary  circulation  has  practically 
ceased  in  the  consolidated  areas.  The  blood  supply  of  these  areas 
may  be  solely  through  the  bronchial  arteries,  the  high-pressure 
supply  from  which  joins  the  pulmonary  circulation.  This  inference 
has  recently  been  confirmed  by  Gross,10  who  found  by  means  of 
X-ray  photographs  of  lungs  injected  with  an  injection  mass 
opaque  to  X-rays,  that  the  pulmonary  vessels  are  nearly  blocked 
off  in  the  consolidated  parts  in  pneumonia.  In  the  unaffected  parts 
of  the  lungs,  the  oxygen  seems  to  penetrate  the  alveolar  walls 
readily  enough  in  pneumonia.  Where  anoxaemia  becomes  danger- 
ous in  croupous  or  disseminated  pneumonia  it  seems  usually  to  be 
failure  of  the  respiratory  center  and  consequent  shallow  breathing 
that  is  mainly  responsible  for  the  anoxaemia. 

The  fact  that  in  pneumonias  of  all  kinds  the  arterial  blood  is 
commonly  more  or  less  imperfectly  saturated  with  oxygen  has 

Gross,  Canadian  Med.  Assoc.  Jourtt.,  p.  632,  1919. 


RESPIRATION  151 

quite  recently  been  shown  directly  by  Stadie,11  who  examined 
samples  of  arterial  blood  drawn  usually  from  the  radial  artery  by 
means  of  a  syringe.  In  normal  persons  he  found  an  average  of 
95  per  cent  saturation  of  the  haemoglobin  with  oxygen ;  and  this 
is  about  what  might  be  expected  in  view  of  what  has  been  said 
above.  In  cases  of  pneumonia  the  saturation  varied  from  95  to 
42  per  cent;  and  as  a  rule  the  cases  where  the  saturation  was 
below  76  per  cent  ended  fatally.  Cardiac  cases  were  soon  after- 
wards investigated  by  Harrop,12  who  found  that  in  many  of  them 
there  was  imperfect  saturation  of  the  arterial  blood.  This  was 
almost  certainly  due,  frequently,  to  partial  failure  of  the  respira- 
tory center  and  consequent  shallow  breathing. 

The  significance  of  these  analyses  will  be  evident  from  what 
has  been  said  in  the  previous  and  present  chapters ;  and  the  danger 
to  a  patient  of  permitting  any  serious  arterial  anoxaemia  to  con- 
tinue when  it  can  be  prevented  is,  I  hope,  already  evident. 

As  anoxaemia  is  such  a  common  and  often  dangerous  condition, 
and  can  frequently  be  combated  by  the  addition  of  oxygen  to  the 
inspired  air,  it  will  be  in  place  to  refer  here  to  clinical  methods 
of  administering  oxygen.  In  the  first  place  it  is  necessary  to  have 
clear  ideas  as  to  the  objects  aimed  at,  in  administering  oxygen.  If 
the  oxygen  is  only  given  to  enable  a  patient  to  surmount  some  quite 
temporary  crisis  due  to  anoxaemia — produced,  it  may  be,  by  one 
of  the  sudden  angina-like  attacks  of  reflex  restriction  of  breath- 
ing referred  above — a  very  simple  method  of  administration  will 
suffice.  A  small  cylinder  of  oxygen  furnished  with  an  india-rubber 
tube  by  means  of  which  a  stream  of  oxygen  may  be  directed  into 
the  patient's  open  mouth  will  suffice;  and  such  an  arrangement 
would  probably  often  be  useful  in  certain  cases,  as  the  oxygen 
could  be  given  promptly  by  a  competent  nurse  at  any  time. 

In  the  great  majority  of  cases,  however,  the  cause  of  the  an- 
oxaemia is  one  which  may  last  for  a  considerable  time,  so  that 
the  administration  of  oxygen,  in  order  to  be  useful,  must  be 
continued.  In  this  connection  it  should  be  clearly  realized  that 
the  object  of  the  oxygen  administration  is  not  simply  palliative, 
but  curative.  By  preventing  the  anoxaemia  we  not  only  avert 
temporarily  a  cause  of  danger  or  damage  to  the  patient ;  but  give 
the  body  an  interval  for  recovery  from  the  original  cause,  what- 
ever it  may  be,  of  the  anoxaemia,  or  for  adaptation.  We  also  break 
a  vicious  circle:  for  if  the  anoxaemia  is  allowed  to  continue,  it 

11  Stadie,  Journ.  of  Exper.  Med.,  XXX,  p.  215,  1919. 
a  Harrop,  Journ.  of  Exper.  Med.,  XXX,  p.  241,  1919. 


152  RESPIRATION 

will  itself  make  the  patient  worse,  or  tend  to  prevent  the  recovery 
which  would  otherwise  naturally  occur.  We  are  not  dealing  with 
a  machine,  but  with  a  living  organism;  and  a  living  organism 
always  tends  to  return  to  the  normal  if  the  opportunity  is  given. 

Oxygen  is  still  often  given  by  methods  which  are  either  quite 
ineffective  or  extremely  wasteful.  One  method  is  to  place  a  funnel 
over  the  patient's  face,  and  allow  some  quite  indefinite  amount  of 
oxygen  to  pass  into  the  funnel.  By  this  method  the  patient  re- 
breathes  a  good  deal  of  expired  air,  but  may  hardly  get  any  of 
the  oxygen,  as  the  latter,  being  heavier,  runs  out  below.  A  far 
better  method  is  to  insert  a  rubber  catheter  or  other  soft  tube  into 
the  patient's  mouth  or  nose,  and  pass  a  stream  of  oxygen  through 
the  tube.  Another  good  method,  when  pure  oxygen  has  to  be  given, 
is  to  allow  the  oxygen  to  pass  at  a  sufficient  rate  into  a  rubber  bag 
connected  with  the  inspiratory  valve  of  an  anaesthetic  mask  placed 
over  the  patient's  mouth  and  nose.  The  patient  inhales  from  the 
bag,  and  exhales  to  the  outside  through  the  expiratory  valve  in 
the  mask. 

In  ordinary  cases  the  patient  does  not  require  pure  oxygen,  but 
only  a  sufficient  addition  to  the  air  of  oxygen  to  prevent  the  an- 
oxaemia. In  any  case  it  would  be  very  undesirable  to  continue  the 
administration  of  pure  oxygen  for  more  than  a  limited  time,  as 
pure,  or  nearly  pure,  oxygen  has  a  slow  irritant  action  on  the 
lungs,  as  will  be  shown  in  Chapter  XII.  If  the  mask  is  left  open 
to  the  air,  so  that  the  patient  can  breathe  as  much  air  as  he  likes, 
and  a  stream  of  oxygen  is  allowed  to  pass  into  the  mask  directly, 
the  oxygen  which  passes  in  during  expiration  is  of  course  wasted. 

It  became  evident  during  the  war  that  an  efficient  apparatus 
for  the  continuous  administration  of  oxygen  with  maximum  econo- 
my in  oxygen  was  greatly  needed,  particularly  in  the  treatment 
of  acute  cases  of  poisoning  by  lung-irritant  gas.  I  therefore  de- 
vised an  apparatus  so  arranged  that  by  a  simple  device  the  patient 
inspired  through  a  face  piece  the  whole  of  the  added  oxygen, 
without  waste  during  expiration,  while  the  proportion  of  oxygen 
could  easily  be  cut  down  or  increased,  according  as  was  needful. 
The  original  form  of  this  apparatus  was  described  in  the  British 
Medical  Journal,  February  10,  1917,  page  181,  after  it  had  already 
been  supplied  extensively  to  the  army  in  France.  Its  use  there  for 
gas  cases  was  initiated,  and'  the  management  of  it  carefully  inves- 
tigated, by  Lieutenant  Colonel  C.  G.  Douglas  of  Oxford.  Other 
well-known  medical  officers  also  made  very  valuable  observations 
on  the  effects  of  oxygen  inhalation.  The  results,  particularly  in 


RESPIRATION 


153 


gas  cases,  were  strikingly  successful;  and  practically  continuous 
administration  could  easily  be  carried  out  over  the  two  or  three 
days  during  which  there  was  danger  from  anoxaemia.  Patients 
can  sleep  comfortably  during  the  administration. 

The  apparatus  was  afterwards  simplified,  with  the  special  object 
of  making  it  both  easy  for  a  nurse  to  handle,  and  available  for 
front  line  and  stretcher  work,  including  treatment  of  "shock" 
cases.  Figure  50  shows  the  arrangement  of  the  apparatus.  It  con- 
sists of :  ( I )  an  oxygen  cylinder  provided  with  an  easily  worked 


f/ICf 

p/ece 


Figure  50. 
Apparatus  for  administering  oxygen. 

and  efficient  main  valve;  (2)  a  pressure  gauge  showing  how  much 
oxygen  is  in  the  cylinder;  (3)  a  reducing  valve  which  reduces 
the  pressure  to  a  small  amount  which  remains  constant  till  the 
cylinder  is  exhausted;  (4)  a  graduated  tap  indicating  the  flow  of 
oxygen  in  liters  per  minute;  (5)  thick- walled  rubber  tubing  con- 
veying the  oxygen  to  the  patient  and  a  light  rubber  bag;  (6)  a 
face  piece  with  a  minimum  of  dead  space,  and  provided  with 
elastic  straps  and  a  pneumatic  cushion  which  can  be  taken  off  for 
disinfection. 

The  patient  can  inspire  and  expire  freely  through  an  opening 
in  which  there  is  a  rubber  flap  to  cause  a  very  slight  resistance. 
During  expiration  the  oxygen  collects  in  the  bag,  and  is  sucked 
into  the  face  piece  at  the  beginning  of  inspiration.  From  the  move- 
ments of  the  bag  it  can  be  seen  at  any  time  whether  the  patient 
is  receiving  the  oxygen.  To  put  the  apparatus  in  action  the  main 
valve  is  opened  freely,  and  the  tap  is  adjusted  to  give  2  liters  a 
minute  or  whatever  greater  or  less  amount  suffices.  With  a  de- 


154  RESPIRATION 

livery  of  2  liters  a  minute  a  40- foot  cylinder  would  last  nearly 
ten  hours. 

The  effects  of  continuous  oxygen  inhalation  with  this  apparatus 
on  the  arterial  blood  in  pneumonia  and  bronchitis  have  quite 
recently  been  investigated  by  Meakins.13  He  found  that  with  2 
liters  a  minute  the  percentage  saturation  of  the  haemoglobin  in  a 
pneumonia  case  with  almost  complete  consolidation  of  one  lung 
rose  from  82  per  cent  to  91  per  cent,  but  went  back  on  stopping  the 
oxygen  to  84  per  cent,  slight  cyanosis  returning  also.  On  then 
giving  3  liters  a  minute,  the  saturation  rose  to  97  per  cent,  which 
is  2  per  cent  above  the  normal  value  for  healthy  persons.  In  a 
bronchitis  case  with  slight  cyanosis  and  orthopnoea,  the  satura- 
tion rose  from  88.6  to  97.0  per  cent  on  giving  2  liters  a  minute, 
and  the  cyanosis  and  orthopnoea  disappeared.  In  a  normal  man 
the  saturation  rose  from  95.6  to  98.1  on  giving  2  liters  a  minute. 

The  plan  of  treating  patients  in  an  air-tight  chamber  contain- 
ing a  high  percentage  of  oxygen  was  introduced  towards  the  end 
of  the  war  at  Cambridge  under  Barcroft's  direction;14  and  a 
similar  chamber  was  erected  at  Stoke-on-Trent.  Favorable  results 
were  obtained  in  chronic  cases  of  gas  poisoning,  as  might  be 
anticipated  in  view  of  the  disturbed  nervous  control  of  breathing, 
already  described  in  Chapters  III  and  VII.  It  now  seems  evident 
that  the  administration  of  air  enriched  with  oxygen  is  likely  to 
be  successfully  introduced  in  the  treatment  of  various  illnesses 
in  which  arterial  anoxaemia  is  present. 

During  considerable  muscular  exertion  the  rate  at  which  oxy- 
gen has  to  penetrate  from  the  alveoli  into  the  blood  is  enormously 
increased.  Hence  it  is  during  muscular  work  that  we  should  ex- 
pect to  find  any  signs  of  anoxaemia  in  healthy  persons  breath- 
ing normal  air  at  normal  atmospheric  pressure.  That  a  certain 
amount  of  anoxaemia  is  commonly  produced  can  be  shown 
indirectly  in  various  ways.  In  the  first  place  the  alveolar  CO2 
pressure,  particularly  in  some  persons,  does  not  rise  during  mus- 
cular exertion  in  the  proportion  that  would  be  expected  if  the 
increased  breathing  were  simply  due  to  the  increased  production 
of  CO2  and  consequent  rise  in  the  alveolar  CO2  pressure.  Thus  in 
the  experiments  of  Priestley  and  myself,  my  own  alveolar  CO2 
pressure  rose  only  by  .13  per  cent,  in  place  of  an  expected  rise  of 

11  Meakins,  Brit.  Med.  Journ.,  March  5,  1920.  A  number  of  further  cases  have 
still  more  recently  been  recorded  by  Meakins,  Journ.  of  Pathol.  and,  Bacter.,  XXIV, 
p.  79,  1921. 

14  Barcroft,  Dufton,  and  Hunt,  Quarterly  Journ.  of  Medicine,  XIII,  p.  179, 
1920. 


RESPIRATION 


155 


about  .8  per  cent,  if  the  increased  breathing  had  been  due  to  CO2 
alone;  while  in  the  case  of  Priestley  (who  was  in  much  better 
physical  training  than  I  was)  the  rise  was  .44  per  cent  in  place  of 
an  expected  rise  of  about  .56.  I  have  since  then  frequently  found 
that  my  alveolar  CO2  pressure  does  not  rise  appreciably  with 
muscular  exertion,  and  falls  if  the  exertion  is  very  great;  though 
in  younger  men  there  is  almost  always  a  marked  rise,  as  in  the 
experiments  on  Douglas,  mentioned  in  Chapter  II.  The  absence 
of  a  rise  in  me  when  ordinary  air  is  breathed  is  not  due  to  the 
formation  of  lactic  acid  referred  to  in  Chaper  VIII.  I  found  in 
1917,  however,  that  there  is  a  well-marked  rise  when  a  little  oxy- 
gen is  added  to  the  inspired  air.  The  failure  of  my  alveolar  CO2 
to  rise  was  therefore  due  apparently  to  slight  anoxaemia  during 
muscular  exertion. 

It  has  for  long  been  well  known  to  engineers  that  men  perform 
hard  physical  work  more  easily  when  they  are  working  in  com- 
pressed air.  This  was  very  evident,  for  instance,  during  the  work 
on  the  Blackwall  tunnel  under  the  Thames,  which  I  visited  about 
25  years  ago.  At  the  existing  air  pressure  the  alveolar  oxygen 
pressure  would  have  3^/2  times  its  normal  value.  In  breathing 
nearly  pure  oxygen  while  wearing  a  mine  rescue  apparatus,  I 
share  the  very  common  experience,  that  in  spite  of  the  weight  of 
the  apparatus,  heavy  exertion,  such  as  walking  very  fast,  is  much 
easier.  On  the  other  hand,  even  a  very  moderate  increase  in  alti- 
tude increases  considerably  the  panting  on  exertion. 

Some  years  ago  Hill  and  Flack15  published  a  number  of  ob- 
servations on  the  apparent  effects  of  oxygen  before  and  after 
muscular  exertion.  Many  of  their  observations  were  concerned 
with  very  striking  effects,  already  referred  to,  of  oxygen  in  pro- 
longing the  time  during  which  the  breath  can  be  held.  They 
showed  that  this  effect  is  just  as  marked  when  exertion  is  per- 
formed with  the  breath  held  as  during  rest.  They  also  found  that 
oxygen  given  during  the  distress  immediately  following  severe 
exertion  has  a  distinct  effect  in  raising  the  blood  pressure,  improv- 
ing the  pulse,  and  alleviating  the  distress.  This  indicates  that  a 
raised  partial  pressure  of  oxygen  in  the  alveolar  air  increases  the 
oxygenation  of  the  blood,  and  that  part  of  the  distress  caused  by 
severe  muscular  work  is  caused  by  deficient  oxygenation  of  the 
arterial  blood.  I  am  unable  to  agree,  however,  with  their  further 
conclusion  that  when  oxygen  is  breathed  a  large  amount  of  free 

15  Hill  and  Flack,  Journ.  of  PhyswL,  XXXVIII,  Pro.  PhyswL  Soc,,  p.  xxviii, 
1909 ;  and  XL,  p.  347,  1910. 


156  RESPIRATION 

oxygen  is  stored  in  the  blood  and  tissues,  and  that  for  this  reason 
a  man  who  has  breathed  oxygen  for  a  time  has  a  distinct  physio- 
logical advantage  as  regards  performance  of  work  over  a  man 
who  has  simply  breathed  air.  Douglas  and  I  found16  that  if  oxy- 
gen is  breathed  quietly  before  an  exertion  there  is  no  physiological 
advantage  if  the  breath  is  not  held.  The  extra  oxygen  in  the  lungs 
is  quickly  washed  out  by  the  breathing,  and  there  is  nothing  to 
indicate  the  existence  of  any  other  extra  store  of  oxygen  in  the 
body.  If,  however,  the  breathing  is  forced  before  the  exertion, 
there  is  considerable  advantage  whether  air  or  oxygen  is  breathed 
during  the  forced  breathing ;  and  this  advantage  is  due  simply  to 
washing  out  of  CO2.  As  will  be  shown  in  Chapter  XII,  the  tis- 
sues and  venous  blood  cannot  become  highly  saturated  with  oxy- 
gen when  this  gas  is  simply  breathed  at  ordinary  atmospheric 
pressure;  and  if  oxygen  had  any  appreciable  effect  apart  from 
that  due  to  the  actual  presence  of  an  increased  percentage  of  oxy- 
gen in  the  lungs  the  result  would  be  very  unintelligible. 

A  clear  and  striking  light  has  been  thrown  on  this  subject  by 
some  recent  experiments  by  Dr.  Henry  Briggs.17  He  found  that 
when  equal  work  is  done  on  a  Martin's  ergometer  the  percentage 
of  CO2  in  the  expired  air  is,  in  persons  not  in  good  physical  train- 
ing, considerably  higher  when  air  rich  in  oxygen  is  breathed  than 
when  ordinary  air  is  breathed.  In  persons  in  the  best  physical 
training,  on  the  other  hand,  there  is  practically  no  difference  until 
the  work  done  is  very  excessive.  The  following  table  is  from  his 


PERCENTAGE  COa  IN  EXPIRED  AIR 

Work  in  foot  pounds 

Subject  A 

Subject 

B 

per  minute 

Breathing 

Breathing 

Breathing 

Breathing 

Pedaling  with  brake  off 

air 

oxygen 

air 

oxygen 

3-9 

4-1 

4-4 

4-5 

3,000 

4-65 

5.25 

5-3 

5.45 

6,000 

4-7 

5-8 

6.2 

6.2 

9,000 

4-3 

5-8 

6.1 

6.3 

10,000 

4.1 

5-7 

6.0 

6.2 

12,000 

5-6 

6.0 

"  Douglas  and  Haldane,  Journ.  of  Physiol.,  XXXIX,  Proc.  Physiol.  Soc.,  p.  i, 
1909. 

17  Briggs,  Henry — Fitness  and  breathing  during  exertion,  /.  Physiology,  Vol.  53, 
1919-1920,  Proc.  Physiological  Soc.,  p.  38-40. 


RESPIRATION 


157 


paper.  Subject  A  was  out  of  training,  and  Subject  B  in  good 
training. 

The  reason  why  anoxaemia  is  absent  in  persons  who  are  in 
good  training  will  be  discussed  in  Chapter  IX. 

There  can  be  little  doubt,  in  view  of  all  the  evidence  adduced 
above,  that  muscular  work  produces  some  degree  of  anoxaemia 
in  untrained  persons,  and  that  the  anoxaemia  increases  with  the 
work.  The  anoxaemia  can  hardly  be  due  to  any  other  cause  than 


LITERS  GAS  INSPIRED  PER  MINUTE 

Subject  A 
Breathing        Breathing 

Subject  B 
Breathing          Breathing 

air 

oxygen 

atr 

oxygen 

12 

25 

13 
22.5 

14 
20 

II 

18 

40 

33 

27 

27 

54 
57 

43 
46 

37 
40-5 
50 

37 
40.5 
48 

that  the  blood  is  passing  through  the  lungs  so  quickly  that  suffi- 
cient oxygen  to  saturate  the  haemoglobin  has  not  time  to  pass  in 
through  the  alveolar  epithelium,  just  as  occurs  to  a  far  greater 
extent  even  during  rest  in  a  case  of  phosgene  poisoning. 

Another  possible  explanation  might  perhaps  suggest  itself,  and 
seems,  indeed,  to  be  suggested  in  Chapter  XI  of  Mr.  Barcroft's 
book,  "The  Respiratory  Functions  of  the  Blood."  This  is  that  the 
velocity  of  the  chemical  reaction,  which  occurs  when  haemoglobin 
comes  into  contact  with  oxygen  at  a  certain  partial  pressure  of 
oxygen,  is  so  low  that  there  is  not  time  for  the  change  to  complete 
itself  in  the  lungs  during  muscular  exertion.  The  rate  at  which 
haemoglobin  takes  up  oxygen,  or  oxyhaemoglobin  gives  it  off, 
in  presence  of  a  certain  partial  pressure  of  oxygen  is  so  extremely 
rapid  that  at  present  we  have  no  means  of  measuring  it.  We  can 
form  some  conception  of  what  must  be  the  velocity  if  we  consider 
what  is  happening  in  the  circulation  of  a  small  warm-blooded 
animal,  such  as  a  mouse  or  bird.  As  was  shown  by  Dr.  Florence 
Buchanan18  the  pulse  rate  of  such  an  animal  is,  even  during  rest, 

"Buchanan,  Journ.  of  Physiol,,  XXXVII,  Proc.  Physiol.  Soc.,  p.  bcxix,  1908; 
and  XXXVIII,  Proc.  Physiol.  Soc.,  p.  Ixii,  1909. 


158  RESPIRATION 

about  700  to  800  a  minute.  A  volume  of  blood  equal  to  the  whole 
of  that  in  the  animal  will  pass  round  the  circulation  in  one  or  two 
seconds  during  exertion,  so  that  any  portion  of  blood  will  only  be 
present  for  an  instant  in  the  pulmonary  capillaries  in  each  round 
of  the  circulation.  Yet  the  time  is  sufficient  for  the  chemical  change 
to  occur  in  the  blood,  and  doubtless  far  more  than  sufficient,  since 
we  have  to  allow  also  for  the  time  needed  for  the  passage  of  oxy- 
gen through  the  layer  of  living  tissue  separating  the  air  from  the 
blood.  In  man  the  time  available  is  much  greater,  so  that  the 
absolute  velocity  of  the  chemical  change  does  not  come  into  con- 
sideration at  all,  though  of  course  the  relative  rates  at  which  oxy- 
gen is  chemically  associated  with  or  dissociated  from  haemoglobin 
at  varying  partial  pressures  of  oxygen  and  varying  temperatures, 
determine  the  corresponding  dissociation  curves  as  experimentally 
determined. 

A  further  group  of  causes  of  anoxaemia  depends  not  on  defec- 
tive saturation  in  the  lungs,  but  on  defect  in  the  charge  of  available 
oxygen  carried  by  the  arterial  blood,  so  that,  with  the  existing 
rate  of  circulation,  the  oxygen  pressure  in  the  systemic  capillaries 
falls  too  low.  Of  this  group,  carbon  monoxide  anoxaemia  will  be 
considered  first. 

The  laws  of  combination  of  carbon  monoxide  with  haemoglobin 
have  already  been  discussed  in  Chapter  IV.  My  own  interest  in 
carbon  monoxide  arose  out  of  my  connection  with  coal  mining,  as 
it  had  become  evident  to  me  that  carbon  monoxide  poisoning  was  a 
common  occurrence,  and  I  wished  to  understand  it  as  thoroughly 
as  possible.  When  Claude  Bernard  discovered  the  combination  of 
CO  with  haemoglobin  he  attributed  death  from  CO  poisoning  to 
the  anoxaemia  resulting  from  the  fact  that  CO  displaces  the  oxy- 
gen of  oxyhaemoglobin.  CO  was,  however,  very  generally  be- 
lieved to  have  other  physiological  actions  than  those  of  anoxaemia, 
and  my  first  experiments  were  made  with  a  view  to  clearing  this 
matter  up. 

To  put  the  matter  to  the  test,  I  devised  the  following  experi- 
ment19 (Figure  51).  A  mouse  was  dropped  into  a  thick  glass 
measuring  vessel  filled  with  pure  oxygen,  and  the  pressure  of 
oxygen  in  this  cylinder  was  then  raised  to  two  atmospheres  by 
connecting  it  with  an  oxygen  cylinder  in  the  manner  shown.  The 
oxygen  was  then  clamped  off  and  another  clamp  opened,  through 
which  the  oxygen  was  directed  into  the  top  of  another  measuring 
vessel  full  of  water,  and  the  water  driven  over  into  a  third  measur- 

"Haldane,  Journ.  of  Physiol.,  XVII,  p.  201,  1905. 


RESPIRATION 


159 


ing  vessel  filled  with  pure  carbon  monoxide,  so  arranged  that  the 
gas  was  driven  into  the  vessel  containing  the  mouse.  The  animal 
was  now  in  a  mixture  consisting  of  two  parts  of  oxygen  and  one 
of  carbon  monoxide,  at  a  total  pressure  of  two  atmospheres  of 
oxygen  and  one  of  carbon  monoxide.  It  could  also  be  killed  by 
drowning  in  this  atmosphere  if  water  was  forced  over. 

My  calculation  was  that  in  the  presence  of  two  atmospheres  of 
oxygen  the  animal  would  have  in  simple  solution  sufficient  oxy- 
gen in  its  arterial  blood  to  supply  the  oxygen  requirements  of  its 
tissues,  at  any  rate  during  rest;  and  that  it  would  thus  be  inde- 
pendent of  the  oxygen  supply  shut  off  through  the  action  of  the 


Figure  51. 
Apparatus  for  exposing  mouse  to  atmosphere  of  oxygen  and  CO. 

CO,  with  which  the  haemoglobin  would  be  almost  completely 
saturated.  If,  however,  the  CO  had  any  toxic  action  apart  from 
its  action  in  producing  anoxaemia  this  action  would  certainly 
manifest  itself  at  once,  since  the  partial  pressure  of  the  CO  was 
100  per  cent  of  an  atmosphere,  whereas  in  CO  poisoning  as  ordi- 
narily met  with  in  non-fatal  cases,  the  partial  pressure  of  CO 


160  RESPIRATION 

is  not  more  than  about  0.2  per  cent  of  an  atmosphere.  The  amount 
of  free  oxygen  which  would  go  into  solution  in  blood  at  the  body 
temperature  with  an  atmospheric  pressure  of  two  atmospheres  is 
4.2  volumes  per  100  cc.  of  blood,  which  is  just  about  as  much  as  is 
ordinarily  taken  from  the  blood  as  it  passes  through  the  tissues 
(see  Chapter  X). 

The  mouse  remained  quite  normal  and  seemingly  unconcerned, 
except  that  when  it  exerted  itself  in  climbing  up  the  jar  it  seemed 
to  become  more  easily  tired  than  usual.  Thus  CO  has  no  appreci- 
able physiological  action  except  that  of  producing  anoxaemia. 
It  is,  physiologically  speaking,  an  indifferent  gas,  like  nitrogen, 
hydrogen,  or  methane,  and,  like  these  gases,  only  acts  physio- 
logically by  cutting  off  the  supply  of  oxygen.  Its  only  specific 
physiological  action,  so  far  as  I  am  aware,  is  that  it  has  a  slight 
garlic-like  odor.  It  is  not  an  "odorless  gas"  except  to  those  who 
are  afraid  even  to  smell  it  on  account  of  the  mythical  properties 
commonly  attributed  to  it.  Animals  which  have  no  haemoglobin 
pay  no  more  attention  to  CO  than  to  nitrogen.  I  kept  a  cockroach 
for  a  fortnight  in  an  atmosphere  consisting  of  80  per  cent  of  CO 
and  20  per  cent  of  oxygen,  and  it  remained  perfectly  well.  CO  is 
not  oxidized  or  otherwise  decomposed  in  the  living  body  of  any 
animal.20  It  passes  in  by  the  lungs  and  passes  out — far  more 
rapidly  than  is  generally  supposed — by  the  lungs,  without  there 
being  the  smallest  loss.  For  this  and  other  reasons  it  is  a  most 
valuable  physiological  reagent. 

The  popular  idea  that  CO  remains  for  long  in  the  blood  is  based 
simply  on  failure  to  realize  the  nature  of  the  symptoms  which  fol- 
low severe  or  long-continued  anoxaemia.  In  the  light  of  present 
knowledge  it  is  childish  to  suppose  that  as  soon  as  anoxaemia  is 
relieved  a  patient  will  recover,  or  that  anoxaemia  is  in  itself  a 
trifling  matter  if  life  is  not  immediately  imperiled.  If  there  were 
only  one  clinical  lesson  derived  from  a  perusal  of  this  book,  I  hope 
it  would  be  that  anoxaemia  is  a  very  serious  condition,  the  con- 
tinuance of  which  ought  to  be  prevented  if  at  all  possible. 

The  properties  of  CO  as  a  poison  can  now  in  the  main  be  under- 
stood in  the  light  of  preceding  chapters.  As  the  molecular  affinity 
of  haemoglobin  for  CO  is  enormously  more  powerful  than  its 
affinity  for  oxygen,  it  is  evident  that  a  very  small  proportion  of 
CO  in  the  air  is  capable  of  saturating  the  blood  to  a  noticeable 
extent.  The  proportion  of  oxygen  in  dry  alveolar  air  is  about  14 

20  For  experiments  and  references  on  this  subject  see  Haldane,  Journ.  of  PAysiol., 
XXV,  p.  225,  1899,  and  M.  Krogh,  Pfliiger's  Archiv,  162,  p.  94,  1915. 


RESPIRATION  161 

per  cent,  and  the  affinity  of  haemoglobin  for  CO  (in  my  own  case 
at  least)  is  about  300  times  its  affinity  for  oxygen.  It  follows  that, 
if  we  assume  for  the  moment  that  the  oxygen  pressure  of  the  blood 
is  that  of  the  normal  alveolar  air,  the  blood  will  gradually  become 

half-saturated  with  CO  if  air  containing  — —  =  .047  per  cent  of 

300 

CO  is  breathed  continuously  for  a  sufficient  time.  If  the  per- 
centage is  .0235  per  cent,  the  final  saturation  will  only  be  one 
third ;  and  if  the  percentage  is  .012  the  saturation  will  be  a  fourth ; 
and  so  on.  If  pure  air  were  again  breathed  the  CO  would  be  ex- 
pelled from  the  body  through  the  unbalanced  action  of  the  al- 
veolar oxygen  pressure  in  expelling  CO  from  its  combination.  The 
rates  of  absorption  and  of  elimination  of  the  CO  can  also  be 
calculated  on  the  same  principles  from  the  mean  percentage  of 
CO  in  the  alveolar  air,  allowing  for  the  fact  that  as  the  haemo- 
globin approaches  the  balancing  saturation  the  rate  of  absorption 
will  gradually  fall  off;  and  similarly  the  rate  of  elimination  will 
gradually  fall  off  as  the  blood  loses  CO.  As  will  be  shown  in 
Chapter  IX,  however,  this  theoretical  course  of  events  is  pro- 
foundly modified  by  active  secretion  of  oxygen  inwards  by  the 
lung  epithelium. 

It  is  evident  also  that  in  air  abnormally  poor  in  oxygen  a  given 
percentage  of  CO  will  become  more  poisonous,  and  in  air  ab- 
normally rich  in  oxygen  less  poisonous.  This  I  verified  experi- 
mentally on  animals.  It  remained  to  ascertain  in  man  what  effects 
corresponded  to  a  given  saturation  of  the  haemoglobin ;  and  this  I 
ascertained  by  experiments  on  myself,21  using  for  the  purpose  the 
carmine  titration  method  referred  to  in  Chapter  IV,  and  fully 
described  in  its  latest  form  in  the  Appendix. 

I  found  in  these  experiments  that  no  particular  effect  was  ob- 
served until  the  haemoglobin  was  about  20  per  cent  saturated.  At 
about  this  saturation  an  extra  exertion,  such  as  running  upstairs, 
produced  a  very  slight  feeling  of  dizziness  and  some  extra  palpita- 
tion and  hyperpnoea.  At  about  30  per  cent  saturation  very  slight 
symptoms,  such  as  slight  increase  of  pulse  rate,  deeper  breathing, 
and  slight  palpitations,  became  observable  during  rest,  and  run- 
ning upstairs  was  followed  in  about  half  a  minute  by  dizziness, 
dimness  of  vision,  and  abnormally  increased  breathing  and  pulse 
rate.  At  40  per  cent  saturation  these  symptoms  were  more  marked, 
and  exertions  had  to  be  made  with  caution  for  fear  of  fainting. 
At  50  per  cent  saturation  there  was  no  real  discomfort  during 

21Haldane,  Journ.  of  PhyswL,  XVIII,  p.  430,  1895. 


1 62  RESPIRATION 

rest,  but  the  breathing  and  pulse  rate  were  distinctly  increased, 
vision  and  hearing  impaired,  and  intelligence  probably  greatly 
impaired.  It  was  also  hardly  possible  to  rise  from  the  chair  with- 
out assistance.  Writing  was  very  bad,  and  spelling  uncertain. 
Movements  were  very  uncertain,  and  it  was  difficult  to  recognize 
objects  distinctly  or  estimate  their  distance  correctly,  so  that  things 
a  long  way  off  were  grasped  at  in  vain.  Attempts  to  go  any  distance 
caused  failure  of  the  legs  and  collapse  on  the  floor.  In  one  experi- 
ment the  saturation  reached  56  per  cent.  It  was  then  hardly 
possible  to  stand,  and  impossible  to  walk.  After  each  of  these 
experiments  the  saturation  of  the  blood  fell  rapidly  when  fresh 
air  was  breathed ;  and  within  three  hours  the  saturation  had  fallen 
below  20  per  cent. 

Shortly  after  these  experiments,  I  examined  the  bodies  of  a 
large  number  of  men  who  had  been  killed  in  colliery  explosions, 
and  found  that  nearly  all  had  died  of  CO  poisoning.  The  satura- 
tion of  the  haemoglobin  with  CO  was  usually  about  80  per  cent, 
but  in  some  cases  not  more  than  60  per  cent.  In  fatal  cases  of 
poisoning  by  lighting  gas  Lorrain  Smith  found  similar  satura- 
tions. 

The  general  similarity  between  the  symptoms  of  CO  poisoning 
and  those  of  anoxaemia  produced  in  other  ways  is  evident;  and 
the  after-symptoms  appear  to  be  identical  with  those  of  mountain 
sickness  and  related  disorders.  There  is,  however,  a  difference 
between  the  symptoms  of  CO  poisoning  and  those  of  anoxaemia 
produced  by  imperfect  oxygenation  of  the  arterial  haemoglobin. 
This  difference  lies  in  the  fact  that  in  CO  poisoning  fainting,  or  a 
tendency  to  fainting,  is  much  more  prominent  than  respiratory 
distress.  A  man  at  a  high  altitude  pants  excessively  on  exertion, 
but  does  not  easily  faint.  A  man  suffering  from  CO  poisoning 
faints  very  readily  on  exertion,  and  the  tendency  to  dizziness  and 
collapse  is  far  more  prominent  than  the  hyperpnoea.  The  fainting 
on  exertion  is  evidently  due  to  the  fact  that  from  lack  of  the  mass 
of  oxygen  needed  the  heart  cannot  compensate  by  sufficiently 
increased  output  of  blood  for  the  greatly  increased  flow  of  blood 
through  the  working  muscles.  The  blood  pressure  therefore  falls, 
with  the  result  that  the  circulation  to  the  brain  is  diminished  and 
anoxaemia  then  causes  loss  of  consciousness.  But  why  does  this 
occur  so  much  more  readily  in  CO  poisoning?  The  fact  that  it  does 
so  indicates  that  relatively  speaking  the  respiratory  center  is  less 
affected  in  the  anoxaemia  of  CO  poisoning,  in  which  the  mass  of 
oxygen  in  the  blood  is  reduced  but  the  pressure  of  oxygen  in  the 


RESPIRATION  163 

arterial  blood  remains  normal.  That  is  to  say,  with  a  degree  of 
anoxaemia  which  would  not  seriously  affect  the  heart  in  anoxae- 
mia from  imperfect  oxygenation  of  the  available  haemoglobin 
there  will  be  marked  response  to  anoxaemia  in  the  respiratory 
center,  but  not  in  CO  poisoning.  This  points  clearly  to  the  very 
important  conclusion  that  it  is  practically  speaking  to  the  oxygen 
pressure  of  the  arterial  blood  that  the  respiratory  center  responds. 
The  blood  which  bathes  the  receptive  end-organs  (or  whatever 
else  is  sensitive  to  the  respiratory  chemical  stimuli)  of  the  respira- 
tory center  must  therefore  be  blood  which  has  lost  very  little  of  its 
arterial  charge  of  oxygen. 

There  are  other  facts  pointing  in  the  same  direction.  Thus  in 
fainting  or  dizziness  from  fall  of  blood  pressure  there  is  no  im- 
mediate panting,  although  the  anoxaemia  which  immediately 
results  in  the  cerebrum  is  sufficient  to  cause  loss  or  impairment  of 
consciousness.  The  arterial  blood,  however,  remains  normal  as 
regards  its  pressures  of  oxygen  and  CO2  during  fainting;  and  in 
accordance  with  the  conclusion  just  reached,  the  breathing  is  not 
stimulated  till  the  stagnation  of  blood  in  the  respiratory  center  is 
very  marked. 

It  is  to  be  kept  in  mind  that  at  a  moderate  altitude  the  pressure 
of  oxygen  in  the  arterial  blood  is  diminished  far  more  than  the 
mass  of  the  oxygen,  as  expressed  by  the  percentage  saturation  of 
the  haemoglobin.  With  CO  it  is  the  mass  of  oxygen  which  is 
diminished  in  the  blood,  while  the  pressure  may  be  normal. 

It  also  seems  a  priori  probable  that  the  respiratory  center  should 
be  continuously  sampling  and  controlling  the  gas  pressures  of  the 
arterial  blood.  For  it  has  to  act  for  the  whole  body.  Its  function 
is  evidently,  not  to  keep  normal  the  gas  pressures  in  the  capillaries 
of  one  particular  part  of  the  body,  such  as  the  medulla  oblongata, 
but  to  keep  normal  the  arterial  blood  upon  which  every  part  of 
the  body  draws  in  accordance  with  varying  local  requirements. 
It  keeps  the  gas  pressures  normal  just  as  the  heart  keeps  the  blood 
pressure  normal,  so  that  every  part  of  the  body  can  always  indent 
for  arterial  blood  of  standard  quality  and  sufficient  quantity. 

A  further  peculiarity  of  CO  poisoning  is  that  quite  commonly 
consciousness  is  lost  for  long  periods  in  the  poisonous  atmosphere 
without  death  occurring.  Thus  cases  of  CO  poisoning  afford  strik- 
ing opportunities  of  studying  the  effects  of  prolonged  general 
anoxaemia  of  the  brain  and  every  other  organ  in  the  body.  The 
reason  why  death  does  not  occur  more  readily  seems  to  be  that, 
although  the  amount  of  oxygen  transported  by  the  blood  is  dimin- 


164 


RESPIRATION 


ished,  the  oxygen  pressure  in  the  arterial  blood  remains  normal, 
and  as  a  consequence  the  respiratory  center  does  not  rapidly  fail 
in  the  same  manner  as  it  does  when  the  arterial  oxygen  pressure  is 
very  low,  as  explained  in  Chapter  VI.  This  characteristic  seems  to 
be  common  to  all  forms  of  anoxaemia  in  which  the  arterial  oxygen 
pressure  remains  about  normal,  including  anoxaemia  due  simply 
to  a  failing  heart. 

If  the  action  of  CO  were  simply  to  diminish  the  oxygen- 
carrying  power  of  the  haemoglobin,  without  modification  of  the 
properties  of  the  remaining  haemoglobin,  the  symptoms  of  CO 
poisoning  would  be  very  difficult  to  understand  in  the  light  of 
other  knowledge.  Thus  a  person  whose  blood  is  half-saturated 


20 


Pressure  of  02  in  Mm.  of  \\g. 

30  40  50  6.0  70 


80 


90 


g 

° 


&4%526272&         91 

Pressure  of  0,  in  %  of  an  atmosphere 


Figure  52. 

Curve  I,  o  per  cent  saturation  with  CO;  II,  10  per  cent;  III,  25  per  cent; 
IV,  50  per  cent;  V,  75  per  cent. 

with  CO  is  practically  helpless,  as  we  have  just  seen ;  but  a  person 
whose  haemoglobin  percentage  is  simply  diminished  to  half  by 
anaemia  may  be  going  about  his  work  as  usual.  Miners  may  be 
doing  their  ordinary  work  though  their  haemoglobin  percentage 
is  reduced  to  half  or  less  by  ankylostomiasis ;  and  women  may  be 
going  about  their  duties  with  their  haemoglobin  percentage  re- 


RESPIRATION  165 

duced  to  a  third  by  chlorosis.  Even  in  the  extremest  "anaemia," 
with  the  haemoglobin  below  20  per  cent  of  its  normal  value,  and 
the  lips  of  extremest  pallor,  the  patient  is  perfectly  conscious, 
though  hardly  capable  of  any  muscular  exertion. 

The  key  to  this  seeming  paradox  is  furnished  by  the  discovery22 
that  the  oxyhaemoglobin  left  in  the  arterial  blood  when  it  is 
partially  saturated  with  CO  has  its  dissociation  curve  altered  in 
such  a  way  that  the  haemoglobin  holds  on  more  tightly  to  the  oxy- 
gen. The  oxygen  still  present  as  oxyhaemoglobin  is  therefore  less 
easily  available,  so  that  the  oxygen  pressure  in  the  tissues  must 
fall  lower  in  order  to  get  off  the  combined  oxygen.  With  a  given 
amount  of  available  oxygen  in  the  blood  the  physiological  anox- 
aemia is  thus  increased.  Figure  52,  from  a  paper  by  J.  B.  S.  Hal- 
dane,23  shows  the  alterations  in  the  dissociation  curves  of  the 
oxyhaemoglobin  with  varying  percentage  saturations  of  the  blood 
with  CO.  It  will  be  seen,  for  instance,  that  with  50  per  cent  satu- 
ration of  the  blood  with  CO  the  oxygen  pressure  must  fall  to  less 
than  half  the  usual  value,  and  with  75  per  cent  saturation  to  less 
than  a  third,  in  order  to  dissociate  half  the  oxygen  present  in  the 
arterial  blood  as  oxyhaemoglobin.  No  wonder,  therefore,  that  the 
symptoms  of  CO  poisoning  are  much  more  severe  than  those  of  a 
corresponding  simple  deficiency  of  haemoglobin  in  the  blood.  It 
will  be  seen  also  that  the  shape  of  the  dissociation  curve  is  com- 
pletely altered.  The  characteristic  double  bend  (which,  as  already 
seen,  is  of  such  vital  physiological  importance)  in  the  oxyhaemo- 
globin curve  tends  to  disappear  altogether,  so  that  an  enormous 
fall  in  oxygen  pressure  is  needed  to  make  the  bulk  of  the  oxygen 
in  the  oxyhaemoglobin  dissociate. 

In  the  investigations  which  Lorrain  Smith  and  I  made  on  the 
effects  of  continuously  breathing  a  definite  percentage  of  CO  all 
the  experiments  were  made  on  ourselves,  and  in  a  series  which 
was  more  or  less  continuous  from  day  to  day.  From  the  results  of 
these  experiments  we  estimated  that  it  required  about  .05  per  cent 
of  CO  in  the  air  to  produce  the  30  per  cent  saturation  of  the  blood 
which  was  necessary  for  any  very  noticeable  symptoms  of  CO 
poisoning.  In  isolated  experiments  made  later,  however,  we  found 
the  CO  much  more  poisonous,  so  that  it  only  required  about  .02 
per  cent  to  produce  the  required  saturation.  In  the  original  ex- 
periments we  had  become  "acclimatized"  without  knowing  it.  The 

22  Douglas,  J.  S.  Haldane,  and  J.  B.  S.  Haldane,  Journ.  of  Physwl.,  XLIV, 
p.  293,  1912. 

83  J.  B.  S.  Haldane,  Journ.  of  Physiol.,  XLV,  Proc.  Physiol.  Soc.,  p.  xxii,  1912. 


1 66  RESPIRATION 

great  significance  of  this  "acclimatization"  will  be  discussed  in 
succeeding  chapters. 

The  other  gas,  besides  CO,  which  enters  into  molecular  com- 
bination with  haemoglobin  is  nitric  oxide.  But  as  free  nitric  oxide 
combines  at  once  with  the  oxygen  in  air  to  form  yellow  "nitrous 
fumes,"  and  these  are  intensely  irritant  and  produce  very  danger- 
ous inflammation,  nitric  oxide  poisoning  in  the  same  sense  as  CO 
poisoning  is  impossible.  Sir  Humphrey  Davy  nearly  killed  him- 
self when  he  attempted  to  breathe  nitric  oxide  (NO)  at  the  time 
when  he  discovered  the  effects  of  nitrous  oxide,  or  "laughing  gas" 
(N2O).  NO  haemoglobin  is,  however,  formed  to  some  extent  in 
the  living  body  during  poisoning  by  nitrites,  as  was  discovered  by 
Makgill,  Mavrogordato,  and  myself  ;24  and  some  time  after  death 
from  nitrite  poisoning  the  whole  of  the  haemoglobin  becomes 
combined  with  NO.  Hence  the  body  is  red,  just  as  in  a  fatal  case  of 
CO  poisoning,  so  that  the  case  might  easily  be  mistaken  for  CO 
poisoning  on  mere  spectroscopic  examination  of  the  blood.  The 
condition  can  be  distinguished  at  once  by  the  fact  that  the  blood 
and  tissues  remain  red  on  boiling,  just  as  in  the  case  already  al- 
luded to  of  salted  meat. 

Another  cause  of  an  anoxaemia  analogous  to  that  of  CO  poison- 
ing is  present  in  the  case  of  the  action  of  poisons  which  produce 
methaemoglobin  in  the  living  body.  The  first  of  these  to  be  dis- 
covered was  chlorate  of  potash,  which  in  former  times,  before  the 
dangerous  properties  of  chlorates  were  realized,  used  to  be  ad- 
ministered freely  as  an  oxidizing  agent,  and  has  even  been  recom- 
mended as  an  antidote  for  the  anoxaemia  of  high  altitudes.  The 
discovery  that  in  a  fatal  case  of  diphtheria  treated  with  chlorate 
of  potash  the  blood  contained  much  methaemoglobin  drew  atten- 
tion to  the  possible  dangers  from  anoxaemia  in  poisoning  by  any 
of  the  numerous  substances  which  are  capable  of  producing  me- 
thaemoglobin in  the  living  body. 

The  possibilities  of  anoxaemia  being  produced  were  investi- 
gated by  Makgill,  Mavrogordato,  and  myself.  As  ferricyanide 
does  not  penetrate  the  walls  of  the  red  corpuscles,  and  chlorates 
do  not  do  so  in  the  animals  we  were  using,  we  used  chiefly  nitrites 
for  the  experiments;  and  we  did  so  for  the  reason,  partly,  that 
nitrites  have  other  important  physiological  actions  besides  that  of 
producing  methaemoglobin  (in  reality  a  mixture  of  methaemo- 
globin with  a  certain  proportion  of  NO  haemoglobin).  Having 
discovered  the  dose  required  to  produce  death  we  then,  as  soon 

34  Makgill,  Mavrogordato,  and  Haldane,  Journ.  of  Physiol.,  XXI,  p.  160,  1897. 


RESPIRATION 


167 


as  serious  symptoms  began  to  develop  after  administration  of  the 
dose,  placed  the  animals  in  compressed  oxygen.  The  result  was 
that  the  serious  symptoms  disappeared  and  the  animals  recovered. 
If,  however,  they  were  removed  into  ordinary  air,  they  died  at 
once  with  anoxaemic  convulsions.  When  kept  in  the  oxygen  for  a 
sufficient  time,  however,  they  completely  recovered  and  could  be 
returned  to  ordinary  air.  Oxygen  at  ordinary  atmospheric  pres- 
sure was  often  sufficient  to  save  the  animals. 

Having  worked  out  a  method  for  estimating  colorimetrically 
the  proportional  extent  to  which  the  haemoglobin  was  altered  by 
the  poison,  we  then  found  that  the  dangerous  symptoms  depended, 
just  as  in  CO  poisoning,  on  the  extent  of  the  alteration.  It  was 
thus  evident  that  the  cause  of  death,  and  of  the  dangerous  symp- 
toms, was  anoxaemia,  just  as  in  CO  poisoning.  We  also  found  that 
the  methaemoglobin  and  NO  haemoglobin  soon  disappeared,  leav- 
ing the  blood  quite  normal,  if  death  was  averted.  The  methaemo- 


IOO 


70 


^ 


60 

50 


•I 

^  40 
1» 


20 
10 


Mours  offer  srr/'ec{t'o/i 

Figure  53. 
Methaemoglobin  due  to  sodium  nitrate. 

globin  was  simply  reduced  back  again,  just  as  on  the  addition  of 
a  reducing  agent  to  a  methaemoglobin  solution  outside  the  body. 
It  was  also  evident  that  the  reduction  process  was  constantly  going 
on  and  tending  to  neutralize  the  poison  even  while  the  relatively 
large  amounts  of  it  were  still  present  in  the  blood.  In  proportion 


1 68  RESPIRATION 

as  the  poison  was  destroyed  or  excreted  the  reduction  process  got 
the  upper  hand.  There  are,  therefore,  reducing  agents  of  some 
kind  or  another  within  the  corpuscles.  Figure  53  shows  the  per- 
centage conversion  to  methaemoglobin  in  the  blood  of  a  rabbit  at 
intervals  after  a  non-poisonous  dose  of  sodium  nitrite.  It  will  be 
seen  that  after  four  hours  the  blood  had  completely  recovered. 

The  action  of  methaemoglobin-forming  poisons  is  rendered 
evident  at  once  by  the  marked  cyanosis  which  they  produce.  The 
methaemoglobin  has  a  dark  color,  and  the  arterial  blood  becomes 
therefore  of  a  chocolate  or  coffee  color.  This  form  of  cyanosis  may 
become  very  marked  indeed  without  serious  real  symptoms  of  an- 
oxaemia being  present.  Thus  in  acute  poisoning  by  dinitrobenzol 
(an  ingredient  of  certain  explosives)  a  man  may  become  very  blue 
in  the  face  and  yet  be  going  about  as  usual,  although  he  presents 
a  most  alarming  appearance. 

Many  of  the  poisons  which  produce  methaemoglobin  cause,  in 
addition,  radical  decomposition  in  the  haemoglobin,  and  even 
breaking  up  of  the  red  corpuscles.  This  is,  for  instance,  the  case, 
to  a  large  extent,  with  dinitrobenzol,  so  that  there  are  other  colored 
decomposition  products  present  as  well  as  methaemoglobin;  and 
for  the  present  it  is  not  possible  to  specify  their  nature.  Their  pres- 
ence, or  that  of  methaemoglobin,  can,  however,  be  detected  at  once 
on  diluting  a  drop  of  the  blood  till  the  color  begins  to  become 
yellowish,  then  saturating  with  coal  gas  or  CO,  and  comparing 
the  tint  with  that  of  normal  blood  diluted  to  a  corresponding  ex- 
tent and  similarly  saturated.  If  any  colored  decomposition  prod- 
ucts are  present  the  normal  blood  solution  will  be  pinker,  as  the 
CO  does  not  combine  to  give  a  pink  color  with  these  foreign 
substances. 

When  a  poison  causes  solution  of  the  red  corpuscles  (haemo- 
lysis), or  decomposes  the  haemoglobin  beyond  the  methaemo- 
globin stage,  the  haemoglobin  is  lost  to  the  body,  and  "anaemia" 
is  one  result  of  this,  as  well  as  jaundice.  Thus  chronic  poisoning 
by  dinitrobenzol  and  similarly  acting  substances  causes  very  seri- 
ous anaemia.  This  also  results  from  chronic  poisoning  by  arsenu- 
retted  hydrogen,  which  has  the  peculiar  action  of  injuring  the 
walls  of  the  red  corpuscles  and  so  causing  haemolysis,  with  re- 
sulting haemoglobinuria,  jaundice,  and  often  nephritis.  We  are 
thus  brought  to  the  consideration  .of  the  anoxaemia  caused  by 
anaemia,  the  word  "anaemia"  being  taken  to  mean  simply  a 
diminution  in  the  percentage  of  haemoglobin  in  a  given  volume 
of  blood,  whether  the  blood  volume  itself  is  diminished,  or  normal, 


RESPIRATION  169 

or  increased.  As  a  matter  of  fact  the  blood  volume  is  usually  much 
increased  in  "anaemia,"  as  was  first  shown  by  Lorrain  Smith.25 

It  was  found  by  Miss  FitzGerald  that  in  ordinary  cases  of 
anaemia  there  is  no  appreciable  diminution  in  the  alveolar  CO2 
pressure.26  As  will  be  shown  more  fully  in  Chapter  VIII,  a  chronic 
arterial  anoxaemia,  however  slight,  invariably  lowers  the  alveolar 
CO2  pressure  if  time  is  given,  and  if  the  anoxaemia  continues 
during  rest.  The  absence  of  a  lowered  alveolar  CO2  pressure  in 
cases  of  anaemia  is  thus  clear  evidence  of  the  absence  of  anox- 
aemia, in  spite  of  greatly  diminished  oxygen-carrying  capacity  of 
the  blood.  It  is  evident,  therefore,  that  the  circulation  rate  is  much 
increased  in  anaemia  and  this  inference  is  confirmed  by  the  ab- 
sence of  cyanosis.  A  little  consideration  will  show  that  this  in- 
creased circulation  rate,  while  it  serves  to  maintain  the  normal 
oxygen  pressure  of  the  blood  in  the  systemic  capillaries,  will  prob- 
ably not  reduce  too  much  the  pressure  of  CO2  in  the  tissues.  The 
CO2  conveying  power  of  the  blood  in  the  living  body  depends,  as 
shown  in  Chapter  V,  on  the  concentration  of  haemoglobin  present 
in  the  blood,  and  this  concentration  is  greatly  reduced  in  anaemia. 
Diminution  in  the  actual  CO2-conveying  power  of  the  blood  in 
the  living  body  will  therefore  advance  pari  passu  with  the  diminu- 
tion of  the  oxygen-carrying  power.  Thus  (as  shown  in  Chapter 
X)  an  increased  circulation  rate  is  brought  about  by  the  combined 
stimulus  of  diminished  oxygen  pressure  and  increased  CO2  pres- 
sure. This  is  not  so  in  the  case  of  anoxaemia  from  defective  satura- 
tion of  the  haemoglobin  in  the  lungs ;  nor,  for  the  special  reason 
given  above,  in  the  anoxaemia  of  CO  poisoning.  The  reason  why 
imperfect  saturation  of  the  arterial  blood  causes  such  serious 
anoxaemia  in  the  cerebrum  and  tissues  elsewhere,  while  anaemia 
causes  so  little  anoxaemia  (during  rest)  unless  it  is  very  extreme, 
is  probably  bound  up  with  this  difference  as  regards  effects  on 
CO2  pressure  in  the  tissues.  The  matter  will,  however,  be  discussed 
more  fully  in  Chapter  X. 

The  last  cause  of  anoxaemia  to  be  considered  is  that  due  prima- 
rily to  defective  circulation ;  and  it  will  be  referred  to  very  briefly 
here,  as  the  relation  of  circulation  to  respiration  will  be  discussed 
in  Chapter  X.  When  the  blood  pressure  is  very  defective  owing  to 
failure  of  heart  action  or  failing  supply  of  venous  blood  to  the 
heart,  the  inevitable  result  is  failure  in  the  general  circulation  rate, 
and  failure  also  in  the  proper  distribution  of  blood  within  the  body. 


25  Lorrain  Smith,  Trans.  Path.  Soc.  Lond.,  LII,  p.  315. 
86  Journ.  of  Pathol.  and  Bacter.,  XIV,  p.  328,  1910. 


I  ;o  RESPIRATION 

This  must  result  in  anoxaemia  in  the  tissues,  together  with  an 
undue  rise  in  their  CO2  pressure.  But  owing  to  the  combination  of 
these  two  conditions  the  fall  in  oxygen  pressure  and  rise  in  CO2 
pressure  will  both  be  moderate  until  the  slowing  of  circulation  is 
excessive :  for  the  oxygen  will  fall  along  the  steep  part  of  the 
dotted  curve  in  Figure  21,  while  the  CO2  pressure  will  rise  along 
the  thick  line  in  Figure  26.  This  means  that  a  great  diminution  in 
the  charge  of  oxygen  in  the  haemoglobin,  and  consequently  a  very 
considerable  cyanosis,  will  be  possible  with  a  comparative  small 
fall  in  the  oxygen  pressure  or  rise  in  the  CO2  pressure.  Hence 
cyanosis  due  to  slowing  of  the  circulation  is  not  in  itself  such  a 
serious  indication  as  cyanosis  due  to  failing  saturation  of  the  blood 
with  oxygen,  although  of  course  indicative  of  possible  more 
serious  failure  of  the  circulation. 

When  fall  of  arterial  blood  pressure  is. due  to  defective  filling 
of  the  large  veins  leading  to  the  heart,  benefit  may  be  expected 
from  the  intravenous  injection  of  suitable  saline  solution,  as  this 
will  tend  to  fill  up  the  veins,  and  to  bring  about  adequate  filling 
of  the  heart.  A  simple  salt  solution  tends,  however,  to  leak  out 
again  very  quickly  from  the  circulation.  To  remedy  this  defect 
Bayliss27  has  introduced  the  plan  of  adding  gum  to  the  salt  solu- 
tion, the  gum  fulfilling  the  same  function  in  preventing  leakage 
as  the  proteins  normally  present  in  blood  plasma.  This  procedure 
has  proved  very  successful,  and  avoids  the  risks  and  practical 
difficulties  associated  with  transfusion  of  blood  or  liquids  con- 
taining proteins.  For  the  reasons  already  pointed  out,  the  dilution 
of  the  blood  by  the  saline  injection  does  not  cause  anoxaemia. 

As  will  be  pointed  out  in  Chapter  X,  failure  in  the  venous  return 
to  the  heart  may  be  due  to  deficient  pressure  of  CO2  in  the  systemic 
capillaries,  owing  to  excessive  washing  out  of  CO2  in  the  lungs ; 
and  this  excessive  washing  out  may  be  secondary  to  arterial  anox- 
aemia. Arterial  anoxaemia  and  deficiency  of  CO2  may  also  be  the 
cause  of  failure  of  the  heart  muscle.  It  is  probable,  therefore,  that 
in  many  cases  the  vicious  circle  may  be  more  effectively  broken  by 
administration  of  oxygen  or  even  CO2  than  by  injection  of  gum- 
saline  solution  or  transfusion  of  blood;  but  in  other  cases  injection 
or  transfusion  would  quite  clearly  be  required. 

"Bayliss,  Intravenous  Injection  in  Wound,  Shock,  1918. 


CHAPTER  VIII 
Blood  Reaction  and  Breathing. 

IT  has  been  known  for  long  that  the  reaction  of  blood  to  litmus 
paper  is  always  slightly  alkaline,  while  the  living  tissues  are  also 
alkaline,  though  they  change  to  acid  in  dying.  Knowledge  as  to  the 
connection  between  the  blood  reaction  and  normal  breathing  is, 
however,  mostly  of  very  recent  origin ;  and  the  same  may  be  said 
of  knowledge  as  to  the  extreme  exactitude  with  which  the  reaction 
of  the  blood  is  regulated,  and  the  physiological  importance  of  the 
very  slightest  deviation,  from  the  normal  reaction  of  the  blood 
and  tissues. 

That  the  reaction  within  the  body  is  physiologically  regulated 
was  originally  indicated,  not  only  by  the  reaction  of  the  blood  to 
litmus  and  other  indicators  being  always  the  same,  but  also  by  the 
fact  that  on  administration  of  sufficient  doses  of  sodium  bicarbon- 
ate or  other  alkalies  the  urine,  which  is  normally  acid  in  man, 
becomes  alkaline.  The  same  effect  is  produced  by  a  vegetable  diet, 
which  contains  a  large  amount  of  organic  acids  combined  with 
alkali.  The  acids  are  mostly  oxidized  with  formation  of  CO2  within 
the  body,  thus  leaving  alkaline  carbonates,  so  that  the  excess  of 
alkali  must  be,  and  actually  is,  excreted  in  order  that  the  reaction 
within  the  body  may  remain  normal.  In  herbivorous  animals  the 
urine  is  always  alkaline.  On  the  other  hand,  in  carnivorous  ani- 
mals, and  in  man  with  his  usual  mixed  diet,  the  urine  is  acid.  This 
is  because  there  is  an  excess  of  non-volatile  acid  formed  within  the 
body  by  the  oxidation  of.  the  sulphur,  phosphorus,  etc.,  in  the 
food  constituents  and  this  excess  is  partly,  at  least,  got  rid  of  by 
the  kidneys,  and  the  normal  alkalinity  of  the  blood  and  tissues 
thus  preserved. 

More  than  forty  years  ago  an  important  series  of  investigations 
bearing  on  the  physiology  of  the  blood  reaction  was  carried  out 
under  Schmiedeberg's  direction  at  Strassburg.  The  effect  on  rab- 
bits of  the  administration  of  large  doses  of  dilute  hydrochloric  acid 
was  investigated  by  Walter,1  and  it  was  found,  as  one  result,  that 
the  breathing  of  the  animals  was  very  greatly  increased,  becoming 
extremely  deep  as  well  as  more  frequent — the  same  sort  of  effect 
as  is  produced  by  excess  of  CO2,  as  shown  in  Chapter  II.  The 

XF.  Walter,  Archw  /.  exper.  PatAol.  Pharmakol.,  VII,  p.  148,  1877. 


172  RESPIRATION 

animals  also  ultimately  became  comatose,  just  as  is  the  case  when 
CO2  is  in  great  excess ;  and  finally  there  were  signs  of  exhaustion 
of  breathing,  the  breathing  ceasing  before  the  heart  ceased  to  beat. 

Another  very  important  result  reached  in  these  investigations 
was  that  when  the  experiments  were  repeated  on  dogs  it  was  much 
more  difficult  to  produce  the  symptoms,  and  it  was  found  that  the 
amount  of  ammonia  excreted  (in  combination  with  acid)  in  the 
urine  was  increased  greatly.  Under  normal  conditions  the  amount 
of  nitrogen  excreted  as  ammonia  is  small  in  proportion  to  the  total 
excretion  of  nitrogen.  Thus  in  man  the  amount  of  ammonia 
usually  excreted  in  24  hours  is  only  about  0.7  gram  (sufficient, 
however,  to  neutralize  about  2  grams  of  H2SO4),  so  that  only  a 
small  fraction  of  the  total  nitrogen  is  excreted  as  ammonia.  In 
acid  poisoning,  however,  the  fraction  becomes  a  very  much 
larger  one  in  carnivorous  animals  and  in  man.  Walter  found  that 
in  dogs  the  ammonia  excretion  could  be  pushed  up  to  several 
times  the  normal  by  giving  large  doses  of  acid. 

According  to  the  existing  evidence,  which  originated  with 
Schmiedeberg  and  his  pupils,  ammonia  is  converted  into  urea  in 
the  liver.  It  appears,  therefore,  that  when  acid  is  administered  to 
carnivorous  animals  or  men,  ammonia  is  not  converted  into  urea, 
or  else  nitrogen  which  normally  appears  as  urea  is  converted  into 
ammonia  and  goes  to  neutralize  the  acid.  If  ammonia  is  admin- 
istered by  mouth  as  carbonate  it  is  wholly  converted  into  urea,  and 
the  excretion  of  ammonia  by  the  urine  may  be  actually  diminished. 
If,  on  the  other  hand,  the  ammonia  is  administered  in  combination 
with  a  strong  acid  as  a  neutral  salt,  much  of  this  ammonia  appears 
as  salts  of  ammonia  in  the  urine.  Some  is,  however,  converted  into 
urea  in  the  liver,  as  was  recently  shown  definitely  by  perfusion 
experiments.2  It  was  found  that  during  health  the  proportion 
of  ammonia  which  escapes  conversion  into  urea  and  consequently 
appears  in  the  urine  depends  on  the  acid-forming  or  alkali- 
forming  properties  of  the  diet.  Thus  with  a  meat  diet  the  pro- 
portion of  ammonia  is  much  higher  than  with  a  vegetable  diet; 
and  by  administering  alkalies  ammonia  may  be  made  to  disappear 
entirely  from  the  urine. 

The  varying  neutralization  of  acids  by  ammonia  is  therefore 
one  of  the  means  by  which  the  reaction  within  the  body  is  regu- 
lated in  man  and  carnivorous  animals,  while  variation  in  the 
excretion  of  acid  or  alkali  in  the  urine  is  another.  The  former 
means  hardly  exists  in  herbivorous  animals.  But  the  significance 

'Loffler,  Biochem.  Zetischr.,  LXXXV,  p.  230,  1918. 


RESPIRATION  173 

of  the  most  rapid  and  effective  method  of  all — varying  excretion 
of  carbonic  acid  by  the  breathing — remained  hidden  till  quite 
recently,  although  Walter's  experiments  showed  that  there  is  not 
only  a  great  increase  in  the  breathing,  but  the  amount  of  carbonic 
acid  present  in  the  arterial  blood  is  reduced  in  extreme  case  to 
about  a  twelfth  of  the  normal. 

It  was  discovered  by  von  Jaksch3  in  1882  that  where  acetone 
is  present  in  the  urine,  as  in  bad  cases  of  diabetes,  verging  on 
coma,  or  actually  comatose,  considerable  quantities  of  aceto- 
acetic  acid  are  also  present;  and  soon  afterwards  Minkowski4 
found  that  oxybutyric  acid,  a  closely  allied  substance,  is  likewise 
present.  The  excretion  of  ammonia  had  already  been  shown  to  be 
greatly  increased,  as  well  as  the  depth  of  the  breathing  and  the 
acidity  of  the  urine,  just  as  in  acid  poisoning;  and  indeed  it  was 
this  that  led  Minkowski,  and  Stadelmann  before  him,  to  the 
search  for  organic  acids.  Thus  all  the  symptoms  point  to  acid 
poisoning  by  the  acids  mentioned.  Shortly  after  Priestley  and  I 
introduced  our  method  of  investigating  alveolar  air,  Pembrey, 
Beddard,  and  Spriggs  investigated  the  alveolar  air  in  cases  of 
diabetic  coma  at  Guy's  Hospital,5  and  found  the  alveolar  CO2 
percentage  as  low  as  i.i  per  cent.  It  went  up  and  down  as 
the  patient  emerged  from  or  relapsed  into  coma;  and  the  ad- 
ministration of  sodium  bicarbonate  warded  off  the  attacks  of 
coma,  and  at  the  same  time  kept  the  alveolar  CO2  percentage  from 
falling.  Investigation  of  the  alveolar  CO2  pressure  is  now  a  well- 
recognized  clinical  method  for  estimating  the  gravity  of  symptoms 
in  diabetic  coma  and  other  states  of  "acidosis,"  as  well  as  for 
judging  of  the  effects  of  treatment. 

For  a  long  time  the  degree  of  alkalinity  of  the  blood  was  judged 
from  the  amount  of  acid  which  has  to  be  added  to  a  given  volume 
of  it  or  its  serum  before  an  indicator,  such  as  litmus,  gives  the  tint 
indicative  of  neutrality.  By  this  method  it  was  found  that  the 
blood  in  acid  poisoning  or  diabetic  coma  is  less  alkaline  than 
usual;  and  all  sorts  of  similar  supposed  "acidoses"  have  been  dis- 
covered, although  the  signs  of  physiological  response  to  the  pres- 
ence in  the  body  of  too  much  acid  might  be  more  or  less  absent  or 
even  contradictory.  A  few  years  ago,  however,  it  became  evident 
that  the  amount  of  acid  required  for  neutralization  is  no  reliable 

3  Von  Jaksch,  Bertchte  der  cLeutschen  Chem.  Gesellsch.,  p.  1496,  1882. 

4  Minkowski,  Arch.  f.  exper.   Pathol.  u.  Pharmak.,  XVIII,  pp.   35   and   147, 
1884. 

6  Beddard,  Pembrey,  and  Spriggs,  Journ.  of  Physiol.,  XXXI,  Proc.  Physiol.  Soc.. 
p.  xliv,  1904;  also  XXXVII,  p.  xxxix,  1908. 


174  RESPIRATION 

measure  of  the  blood  alkalinity.  Even  a  strong  solution  of  sodium 
bicarbonate  is  but  feebly  alkaline ;  but  the  amount  of  acid  which 
must  be  added  to  it  to  render  it  neutral  is  as  great  as  if  the  sodium 
were  present  as  caustic  soda,  and  is  thus  no  measure  of  the  actual 
alkalinity  of  the  solution.  The  carbonic  acid  united  with  the  soda 
prevents  it  from  being  at  all  strongly  alkaline,  but  at  the  same  time 
does  not  completely  neutralize  it,  and  all  weak  acids  have  the  same 
properties.  They  may  thus  be  said  to  be  "buffer"  substances,  since 
they  prevent  a  strong  acid  from  neutralizing  at  once  a  weakly 
alkaline  solution.  A  great  deal  of  the  strong  acid  has  to  be  added 
before  the  weak  alkalinity  is  neutralized.  The  same  applies  to  weak 
alkalies,  mutatis  mutandis. 

Now  the  blood  and  tissues  are  full  of  buffer  substances.  In  the 
first  place,  as  already  seen  in  Chapter  V,  carbonic  acid  is  present 
in  combination.  Haemoglobin  and  various  other  proteins  are  also 
present ;  and  it  has  been  well  known  for  a  long  time  that  proteins 
act  as  both  acid  and  alkaline  buffers,  so  that  the  neutral  point  in  a 
solution  containing  proteins  is  very  difficult  to  ascertain  sharply 
by  means  of  ordinary  indicators.  The  color  alters  gradually  in 
either  direction  as  the  neutral  point  for  any  particular  indicator 
is  approached.  It  was  shown  in  Chapter  V  that  in  the  alkaline 
blood  haemoglobin  and  other  proteins  act  as  weak  acids  more  than 
sufficient  in  amount  to  combine  with  the  bases  not  already  com- 
bined with  strong  acids,  and  that  the  presence  of  these  proteins 
along  with  carbonic  acid  determines  the  manner  in  which  the 
alkali  in  blood  takes  up  and  gives  off  CO2  with  varying  partial 
pressures  of  this  gas.  The  amount  of  acid  required  to  produce 
neutrality  is  thus  in  itself  no  measure  of  the  degree  of  alkalinity 
in  blood,  but  depends  on  the  amount  of  the  various  buffer  sub- 
stances, including  carbonic  acid  in  combination  with  alkali ;  and 
they  may  vary  considerably  in  amount  under  different  conditions. 
This  has  been  pointed  out  very  clearly  by  L.  J.  Henderson.6 

It  may  be  desirable  at  this  point  to  remind  the  reader  as  to  the 
conception  of  acidity  and  alkalinity  to  which  chemical  and  physi- 
co-chemical investigation  has  led  during  the  last  thirty  years.  The 
phenomena  of  electrolysis  revealed  to  Faraday  the  fact  that  the 
constituents  of  any  "electrolyte,"  such  as  copper  sulphate,  are 
torn  asunder  during  electrolysis  into  definite  fragments,  of  which 
one  kind  travels  toward  the  anode,  and  the  other  to  the  cathode. 
These  fragments  he  called  "ions,"  because  it  is  their  movement 
towards  either  anode  or  cathode,  and  the  fact  that  each  of  them  has 

"  L.  J.  Henderson,  Ergebn.  der  Physiol.,  VIII,  p.  254,  1909. 


RESPIRATION  175 

a  definite  electrical  charge,  that  determines  the  phenomena  of 
electrolysis  and  the  exact  quantitative  relationship  between-the 
current  passed  through  a  cell  containing  an  electrolyte  in  solution 
and  the  splitting  up  of  the  electrolyte  into  its  constituents.  Van't 
Hoff  and  Arrhenius  brought  Faraday's  conception  into  relation 
with  osmotic  pressure  and  various  other  phenomena  connected 
with  solutions. 

Osmotic  pressure  was  first  measured  accurately  by  the  botanist 
Pfeffer.7  He  used  a  semi-permeable  membrane  (i.e.,  a  membrane 
which  allowed  the  solvent  water,  but  not  the  dissolved  substance, 
to  pass)  which  had  been  originally  discovered  by  Moritz  Traube 
in  i867,8  though  Traube  had  not  seen  how  to  apply  this  membrane 
for  measuring  osmotic  pressures.  Some  years  later  van't  Hoff9 
made  the  brilliant  discovery  that  in  dilute  solutions  of  sugar  and 
other  substances,  the  osmotic  pressure  is  practically  the  same  as 
the  pressure  which  the  solute  would  have  if  its  molecules  were 
present  alone  in  the  gaseous  form  at  the  same  temperature.  There 
must  thus  be  a  fundamental  connection  between  molecular  con- 
centration, osmotic  pressure,  and  gas  pressure ;  also  between  mo- 
lecular concentration  and  the  vapor  pressures,  boiling  points  and 
freezing  points  of  solutions,  as  had  already  been  empirically  shown 
by  the  investigations  in  particular  of  Raoult.  Van't  Hoff  believed 
that  osmotic  pressure,  etc.,  were  due  in  some  way  to  the  molecular 
bombardment  of  the  solute  molecules,  and  therefore  vary  as  their 
concentration  per  liter  of  solution ;  and  this  theory  has  served  for 
the  building  up  of  the  theory  of  solutions  as  it  is  still  represented 
in  current  textbooks  of  physical  chemistry.  In  reality  this  theo- 
retical interpretation  was  not  even  justified  by  Pfeffer's  data  if 
concentration  per  liter  is  considered,  and  breaks  down  entirely  for 
concentrated  solutions.  The  theory  is  also  quite  unintelligible 
mechanically,  since  the  bombardment  pressure  of  the  solute  mole- 
cules would  be  in  the  wrong  direction  for  explaining  the  phe- 
nomena. Hence  many  persons  regarded  van't  Hoff's  theory  with 
the  greatest  suspicion ;  but  the  fact  that  it  seemed  to  answer  ad- 
mirably as  a  means  of  prediction  in  the  case  of  dilute  solutions, 
and  to  cover  an  enormous  mass  of  facts,  has  led  to  its  very  general 
acceptance,  though  other  attempts  have  been  made  to  substitute 
for  it  some  more  intelligible  conception. 

In  iQiS10  I  showed  quite  clearly,  as  I  think,  that  van't  Hoff's 

T  Pfeffer,  Osmottsche  Untersuchungen,  1877. 

8  Traube,  Archiv   f.  (Anat.  «.)  Physiol.,  p.  87,  1867. 

9  Van't  Hoff,  Zeitschr.  f.  physik.  Chemie,  I,  p.  481,  1887. 
"Haldane,  Bio-Chemical  Journal,  XII,  p.  464,  1918. 


1 76  RESPIRATION 

conception  of  osmotic  pressure  was  mistaken.  It  is  neither  the  con- 
centration per  liter  of  the  solute  molecules,  nor  that  of  the  solvent 
molecules,  that  determines  osmosis,  but  the  diffusion  pressure 
of  the  solvent.  Water  passes  through  a  semi-permeable  mem- 
brane into  a  solution,  because  the  diffusion  pressure  of  pure  water 
is  greater  than  that  of  the  diluted  water  in  the  solution.  The 
osmotic  pressure  is  not  the  excess  of  diffusion  pressure  of  water 
outside  the  solution,  but  the  external  mechanical  pressure  required 
to  equalize  the  two  diffusion  pressures,  although  in  sufficiently 
dilute  solutions  this  mechanical  pressure  is  practically  the  same 
as  the  excess  of  diffusion  pressure  of  water. 

In  a  solution,  just  as  in  a  gas  mixture,  the  molecules  are  free 
to  move  about;  and,  just  as  in  a  gas  mixture,  the  mean  free 
space  round  each  molecule  is  the  same  because  the  mean  energy 
of  external  movement  is  the  same  for  each  molecule.  Hence  the 
free  space  in  which  water  molecules  are  free  to  diffuse  is  in  pro- 
portion to  the  total  number  per  liter  of  molecules  present.  This 
space  is  of  course  greater  per  molecule  of  solvent  in  a  solution 
than  in  the  pure  solvent.  Hence  the  pure  solvent  diffuses  into  the 
solution  unless  the  external  pressure  on  the  solution  is  raised 
sufficiently  to  equalize  the  two  diffusion  pressures. 

When  osmotic  pressure,  vapor  pressures,  boiling  points,  etc., 
are  calculated  in  terms  of  this  theory  instead  of  van't  Hoff's  theory, 
the  experimentally  ascertained  values  agree  with  the  theory, 
whereas  this  is  not  the  case,  as  is  now  well  known,  with  van't 
Hoff's  theory,  except  in  the  case  of  very  dilute  solutions.  Thus 
for  solutions  of  cane  sugar,  and  allowing  for  the  fact  that  at 
temperatures  near  o°C.  cane  sugar  is  present  in  solution  as  a  penta- 
hydrate,  the  osmotic  pressures  at  o°C.  calculated  from  the  con- 
centrations on  the  new  theory  and  the  pressures  actually  observed 
by  the  Earl  of  Berkeley  and  Mr.  Hartley  at  Oxford  are  as  follows : 


OSMOTIC  PRESSURE  IN  ATMOSPHERES 

Grams  Cane  Sugar 

Observed 

Calculated 

Calculated  on 

per  100  cc. 

van't  Hoff's  theory 

3-32 

2.23 

2.24 

2.17 

9-59 

6.85 

6.85 

6.29 

18.26 

14.21 

14.17 

11-95 

25.81 

21.87 

21.80 

16.90 

28.13 

24-55 

24.44 

18.41 

54-24 

67.74 

67.66 

35-48 

RESPIRATION  177 

The  vapor  pressures,  boiling  points,  and  freezing  points  of 
sugar  solutions  show  a  similar  agreement  between  observations 
and  the  new  theory,  as  pointed  out  in  detail  in  my  paper. 

To  physiologists  the  main  advantage  of  the  new  theory  is  that, 
as  will  be  pointed  out  in  detail  in  later  chapters,  it  enables  us  to 
utilize  the  kinetic  theory  of  matter  in  unifying  our  conceptions 
of  a  great  number  of  physiological  phenomena. 

The  osmotic  pressures  observed  by  Pfeffer  and  others  for  dilute 
salt  solutions  were  far  greater  than  corresponded  to  van't  Hoff's 
theory.  This  became  quite  intelligible  when  Arrhenius  pointed 
out  in  I88;11  that  the  discrepancy  could  be  cleared  up  on  the  as- 
sumption that  solutions  of  electrolytes  are  ionized  to  a  greater  or 
less  extent.  Their  osmotic  pressures  are  not  merely  due  to  the 
concentration  (or,  in  terms  of  the  new  theory  just  referred  to,  the 
diffusion  pressure)  of  complete  molecules  of  the  solute,  but  also 
to  the  concentrations  of  the  ions  present,  as  indicated  by  the  vary- 
ing electrical  conductivities  of  different  strengths  of  the  solutions. 
This  explanation  of  Arrhenius  was  received  at  first  with  some 
incredulity,  but  is  now  universally  accepted,  as  the  evidence  in 
favor  of  it  is  overwhelming.  A  dilute  solution  of  sodium  chloride, 
for  instance,  is  not  now  regarded  as  a  solution  of  NaCl  molecules, 
but,  practically  speaking,  of  sodium  and  chlorine  ions.  Similarly 
a  dilute  solution  of  hydrochloric  acid  is  a  solution  of  hydrogen  and 
chlorine  ions. 

lonization  may  be  regarded  as  a  tearing  apart  of  the  molecules 
of  the  electrolyte  in  solution  on  account  of  the  molecular  affinity 
of  H2O  molecules  for  the  atoms  of  the  electrolyte  molecules ;  and 
in  accordance  with  this  conception  the  ions  are  not  stray  atoms  or 
other  fragments  of  molecules,  but  molecular  compounds  with 
molecules  of  water.  In  pure  water  itself  the  molecules  are  also  to 
a  certain  extent  ionized,  as  indicated  by,  among  other  things,  the 
conductivity  of  pure  water.  The  products  of  this  ionization  are 
hydrogen  and  hydroxyl  (HO)  ions,  combined  with  molecules  of 
water. 

The  acidity  of  a  solution  is  due  to  preponderance  of  hydrogen 
ions,  and  the  alkalinity  to  preponderance  of  hydroxyl  ions;  and 
when  the  concentrations  of  hydrogen  and  hydroxyl  ions  are  equal 
the  solution  is  neutral.  As,  however,  hydrogen  and  hydroxyl  ions 
are  constantly  reacting  with  one  another  according  to  the  equation 

H  +  HO  *±  H20, 
the  product  of  the  concentrations  of  hydrogen  and  hydroxyl  ions 

11  Arrhenius,  Zeitschr.  f.  -phystk.  Chemie,  I,  p.  631,  1887. 


178  RESPIRATION 

remains  the  same,  in  accordance  with  the  law  of  mass  action,  how- 
ever acid  or  alkaline  a  solution  may  be.  Hence  the  concentration 
of  hydroxyl  ions  diminishes  in  proportion  as  that  of  hydrogen 
ions  increases,  and  vice  versa. 

All  acids  and'  bases  combine  with  one  another  in  chemically 
equivalent  proportions,  but  different  acids  and  alkalies  vary  very 
greatly  in  the  extent  to  which  they  are  ionized.  The  "strengths" 
of  different  acids  and  alkalies  were  found  by  the  electrical  con- 
ductivity method  to  depend  upon  the  extent  of  their  ionization. 
The  "strong"  acid  HC1  is,  for  instance,  very  completely  ionized 
into  hydrogen  and  chlorine  ions,  and  the  "strong"  base  NaHO  is 
similarly  ionized  into  sodium  and  hydroxyl  ions ;  while  "weak" 
acids,  such  as  carbonic  acid,  or  weak  bases,  such  as  ammonia,  are 
very  slightly  ionized. 

Water  itself  is  slightly  ionized  into  hydrogen  and  hydroxyl 
ions,  and  can  thus  act  as  either  a  very  weak  acid  towards  bases  or 
a  weak  base  towards  acids.  In  the  case  of  strong  or  highly  ionized 
acids  and  bases  this  property  of  water  is  practically  of  no  account, 
as  the  ionization  of  water  is  so  very  small ;  but  in  the  case  of  weak 
acids  or  bases  the  water  competes  appreciably  with  the  acid  or 
base.  For  instance  in  the  case  of  potassium  cyanide,  a  compound  of 
an  extremely  weak  acid  with  a  very  strong  base,  the  following  re- 
action occurs : 

KCN  +  H20  *±  KOH  +  HCN. 

Thus  free  KOH  and  free  HCN  are  both  present  in  a  solution  of 
this  salt.  But  the  KOH  is  highly  ionized  into  K  and  HO  ions, 
while  the  HCN  is  hardly  ionized  at  all.  Hence  HO  ions  pre- 
dominate, and  the  solution  is  alkaline.  Carbonic  acid  is  not  such  a 
weak  acid  as  hydrocyanic  acid;  but  the  same  relations  hold,  so 
that  both  carbonates  and  bicarbonates  form  solutions  which  are 
distinctly  alkaline ;  and  bicarbonate  solutions  are  still  slightly 
alkaline,  even  though  much  free  carbonic  acid  is  present,  as  in  the 
case  of  blood  in  the  living  body. 

The  ordinary  indicators  appear  to  be  extremely  weak  acids 
or  bases  which  change  color  on  combination.  When  the  only 
other  acids  or  bases  present  are  strong  ones,  the  change  of  color 
is  of  course  very  sharp ;  but  with  other  weak  acids  or  bases  present, 
the  change  is  gradual  and  the  complete  color  change  does  not 
occur  until  the  solution  is  distinctly  alkaline  or  acid.  This  is  be- 
cause the  indicator  competes  with  other  weak  acids  for  the  base ; 
and  different  indicators  compete  in  varying  degrees.  Thus  dif- 
ferent indicators  turn  with  different  degrees  of  slight  variation 


RESPIRATION  179 

from  the  true  neutrality  point  where  hydrogen  and  hydroxyl  ions 
are  equal  in  concentration,  as  in  pure  water. 

The  relative  diffusion  pressures,  or  (to  use  the  incorrect  lan- 
guage of  the  still  generally  accepted  van't  HofTs  theory  of  osmotic 
pressure,  etc.)  the  relative  concentrations  of  any  particular  sort 
of  ion,  in  different  solutions,  can  be  measured  by  the  differences 
of  potential  communicated  to  a  suitable  electrode  dipped  in  the 
solutions.  Thus  with  a  hydrogen  electrode  hydrogen  ion  con- 
centration can  be  measured  directly;  and  this  method  was  ap- 
plied, soon  after  its  discovery,  to  the  measurement  of  the  hydrogen 
ion  concentration  (and  therefore  indirectly  also  of  the  hydroxyl 
ion  concentration)  of  blood.  The  earlier  attempts  gave  the  result 
that  the  blood  was  neutral  in  reaction,  and  remained  neutral  even 
in  acidosis.  The  physiological  signs  of  acidosis  were,  however, 
very  clear,  as  already  explained.  The  electrometric  method  in  its 
earlier  form  was  thus  far  too  rough  for  physiological  work. 

It  was  mentioned  in  Chapter  I  that  the  experiments  of  Geppert 
and  Zuntz  on  the  hyperpnoea  following-  muscular  contractions  in 
animals  showed  a  great  diminution  in  CO2  and  a  slight  excess  of 
oxygen  in  the  arterial  blood  during  the  hyperpnoea.  They  there- 
fore concluded  that  neither  excess  of  CO2  nor  want  of  oxygen  can 
be  the  cause  of  the  hyperpnoea ;  and  they  sought  for  the  cause  in 
some  acid  substance  present  in  the  blood,  since  acids  were  known 
to  stimulate  the  breathing.  The  search  made  for  the  acid  substance 
did  not,  however,  lead  to  any  definite  result ;  and  the  experiments 
of  Priestley  and  myself  on  man  brought  us  back  to  CO2  as  the 
stimulus  to  the  increased  breathing.  The  improbability  of  any 
organic  acid  being  the  stimulus  to  the  breathing  seemed  to  us  to 
be  in  any  case  very  great.  No  acid  other  than  CO2  is  given  off  in 
the  expired  air,  and  organic  acids,  etc.,  are  not  appreciably  oxi- 
dized in  the  blood  itself.  It  did  not  therefore  seem  possible  to  un- 
derstand how  the  air  hunger  of  muscular  exertion  could  be  re- 
lieved, as  it  undoubtedly  is,  by  increased  breathing.  In  any  case 
the  diminished  proportion  of  CO2  in  the  arterial  blood  in  these 
experiments  was  entirely  discounted  by  the  fact  that  this  dimin- 
ished proportion  continued  to  exist  for  at  least  an  hour  after  the 
hyperpnoea  had  passed  off.  We  thought  that  in  Geppert  and 
Zuntz's  experiments  owing  to  defective  circulation  in  the  artifi- 
cially stimulated  muscles  of  the  animal  some  lactic  acid  had  been 
produced  and  thrown  into  the  blood,  thus  greatly  reducing  its 
power  of  combining  with  CO2.  Thus,  although  the  pressure  of 
CO2  was  perhaps  actually  higher  in  the  arterial  blood  and  caused 


1 8o  RESPIRATION 

hyperpnoea,  the  amount  of  CO2  contained  in  the  blood  was  much 
less.  We  also  thought  that  owing  to  the  diminished  CO2  carrying 
power  of  the  blood  there  might  be  an  increased  rise  of  CO2  pres- 
sure in  the  tissues.  This  explanation  was,  however,  somewhat 
strained  and  unsatisfactory,  as  was  pointed  out  in  Chapter  II.  We 
had  correctly  divined  the  main  cause  of  the  greatly  diminished 
proportion  of  CO2  in  the  arterial  blood  in  those  experiments,  but 
not  the  whole  cause. 

In  a  series  of  experiments  by  Boycott  and  myself  on  the  effects 
of  low  atmospheric  pressure  in  a  steel  chamber  on  the  alveolar 
CO2  pressure12  we  found  that  on  returning  from  low  pressure 
the  alveolar  CO2  pressure,  which  had  been  lowered  by  the  hyperp- 
noea caused  by  the  low  atmospheric  pressure,  did  not  return  at 
once  to  normal,  but  remained  low  for  some  time.  Ogier  Ward, 
who  was  working  in  conjunction  with  us,  found  the  same  thing 
and  in  much  more  marked  and  persistent  degree,  on  returning  to 
ordinary  pressure  after  a  stay  on  Monte  Rosa.13  Galleotti,14  and 
also  Aggazotti,15  had  already  found  that  the  titration  alkalinity  of 
the  blood  is  diminished  by  exposure  to  low  pressure  in  a  steel 
chamber  or  at  high  altitudes.  It  was  also  known  from  older  experi- 
ments made  in  Hoppe-Seyler's  laboratory  by  Araki16  that  in  con- 
ditions of  acute  want  of  oxygen  (CO  poisoning,  etc.)  large  quanti- 
ties of  lactic  acid  are  produced  in  the  body.  Putting  together  all 
these  facts,  and  the  results  of  Walter's  experiments  on  acid  poison- 
ing, we  drew  the  conclusion  that  what  the  respiratory  center  re- 
sponds to  is  the  combined  effect  of  carbonic  acid  and  other  acids  on 
the  reaction  of  the  blood.  It  seemed  no  longer  possible  to  maintain 
the  hypothesis  that  CO2  acts  specifically  in  exciting  the  respira- 
tory center.  The  long  duration  of  the  lowering  of  alveolar  CO2 
pressure  after  exposure  to  want  of  oxygen  seemed  intelligible  on 
the  theory  that  excess  of  lactic  acid  had  been  produced  owing  to 
the  anoxaemia,  and  that  the  sodium  or  potassium  lactate  thus 
formed  had  been  excreted  by  the  kidneys,  thus  robbing  the  body 
of  alkali  and  leaving  the  blood  correspondingly  less  alkaline — a 
deficiency  which  it  required  some  time  to  make  up. 

This  conclusion  was  further  strengthened  by  the  observation  of 
Douglas  and  myself,  that  after  an  excessive  muscular  exertion 

11  Boycott  and  Haldane,  Journ.  of  Physiol.,  XXXVII,  p.  355,  1908. 
"Ogier  Ward,  Journ.  of  PhyswL,  XXXVII,  p.  378,  1908. 
"Galleotti,  Arch.  Ital.  de  BioL,  XLI,  p.  80,   1904. 
"Aggazotti,  Ibid.,  XLIV,  1905. 

"Araki,  Zeitschr.  f.  physiol.  Chemie,  XV,  p.  335,  1908;  also  XVI,  p.  425; 
XVII,  p.  311  ;  XVIII,  p.  422. 


RESPIRATION  jgi 

the  alveolar  CO2  pressure  remains  low  for  about  an  hour.17  We 
attributed  this  to  the  effect  on  the  respiratory  center  of  lactic  acid 


10     15     20    25    30     35    40    45    50    55     60     65     70_   75 


Figure  54. 

®  Blood,  +  Serum,  O  Corpuscles  of  same  sample.  El  Blood, 
X  Serum  of  another  sample.  /  Blood  of  another  sample.  0 
Another  sample  of  blood.  0  Same  sample  with  acetic  acid  added. 

O  8  parts  —  Na2HPO4  and  2  parts—  KH2PO4.   Q  Equal 
IS  IS 

parts  —  Na2HP04  and  KH2PO4.  •  —  KC1  solution. 
15  10 

given  off  into  the  blood  by  muscles  in  which  the  work  had  been 
far  in  excess  of  the  possible  oxygen  supply.  The  correctness  of 

"Douglas  and  Haldane,  Journ.  of  PhysioL,  XXXVIII,  p.  43 1,  1909. 


1 82  RESPIRATION 

this  inference  was  shortly  afterwards  established  by  Ryffel,18  who 
had  meanwhile  worked  out  a  new  and  very  convenient  method  of 
determining  small  amounts  of  lactic  acid  in  blood  and  urine. 

The  methods  of  determining  hydrogen  ion  concentration  in  the 
blood  were  at  that  time  still  too  crude  to  permit  of  testing  these  in- 
ferences by  direct  determinations,  but  shortly  afterwards  the  elec- 
trometric  method  was  greatly  improved  by  Sorensen  and  particu- 
larly by  Hasselbalch  of  Copenhagen.  In  1912  Hasselbalch  and 
Lundsgaard19  published  curves  showing  the  variations  of  hydro- 
gen ion  concentration  with  variations  in  CO2  pressure  at  body 
temperature  in  ox  blood,  and  Lundsgaard20  repeated  the  experi- 
ments with  human  blood.  Figure  54  shows  graphically  their  re- 
sults for  blood  and  other  liquids.  For  convenience'  sake  the  results 
for  hydrogen  ion  concentration  are  plotted,  not  directly  in  terms  of 
gram  molecules  per  liter,  but  in  terms  of  the  negative  power  of  TO 
representing  this  value.  This  mode  of  notation,  introduced  by 
Sorensen,  is  represented  by  the  symbol  PH,  and  since  the  negative 
power  increases  with  diminution  of  hydrogen  ion,  or  increase  of 
hydroxyl  ion  concentration,  the  curve  rises  with  diminution  of 
hydrogen  ion  concentration. 

At  body  temperature  the  point  of  neutrality  corresponds  to  a 
PH  about  6.78,  as  indicated  by  the  thick  line  in  the  figure.  It  will 
be  seen  from  the  curves  that  even  with  a  far  higher  pressure  of 
CO2  than  exists  in  the  living  body  the  neutral  point  is  not 
reached.  This  is  partly  due  to  the  fact  that  the  proportional  ioniza- 
tion  of  carbonic  acid  becomes  less  and  less  with  increasing  con- 
centration, just  as  is  the  case  with  other  acids,  including  even 
strong  ones.  The  lower  curve  (for  neutral  potassium  chloride  solu- 
tion) shows  this  clearly.  Thus  sulphuric  acid  when  pure  is  quite 
devoid  of  acid  properties  and  does  not  attack  metals,  because  it  is 
practically  not  ionized  at  all.  This  can  be  understood  on  the 
theory,  already  alluded  to,  that  ionization  in  aqueous  solutions  is 
brought  about  through  a  reversible  reaction  with  the  water  mole- 
cules. 

The  influence  of  a  buffer  substance  (disodium  phosphate)  in 
hindering  changes  of  hydrogen  ion  concentration  is  shown  very 
strikingly  in  the  two  curves  for  phosphate  solutions.  In  blood,  as 
already  pointed  out,  various  buffer  substances,  including  haemo- 
globin with  other  proteins,  and  the  phosphate  in  the  corpuscles, 
are  present.  The  curve  for  acidified  blood  shows  that  even  when 

18  Ryffel,  Journ.  of  Physiol.,  XXXIX,  Proc.  Physwl.  Soc.,  p.  xxix,  1910. 

19  Hasselbalch  and  Lundsgaard,  Bwchem.  Zeitschr.,  XXXVIII,  p.  77,  1912. 

20  Lundsgaard,  Btochem.  Zeitschr.,  XLI,  p.  247,  1912. 


RESPIRATION  183 

blood  is  rendered  distinctly  acid  these  buffer  substances  still  act 
very  efficiently.  The  haemoglobin  acts  as  an  alkali,  whereas  it 
always  acts  as  an  acid  in  blood  within  the  living  body. 

In  order  to  test  whether  it  is  really  to  difference  in  PH  that  the 
respiratory  center  normally  reacts,  Hasselbalch  made  the  experi- 
ment of  altering  the  resting  alveolar  CO2  pressure  by  changing 
the  diet.  A  meat  diet,  consisting  largely  of  proteins  containing 
sulphur  and  phosphorus  which  break  down  into  free  sulphuric  and 
phosphoric  acid,  is  evidently  an  acid-forming  diet  as  compared 
with  a  vegetable  diet,  which  contains  less  protein  and  a  relative 
abundance  of  salts  of  organic  acids  which  break  up  in  the  body  so 
as  to  yield  carbonates.  Hasselbalch  found  that  with  the  acid  meat 
diet  the  resting  alveolar  CO2  pressure  was  4.4  mm.  lower,  and 
then  proceeded  to  compare  the  PH  of  the  blood  in  the  two  condi- 
tions. The  results  were  as  follows  :21 


Alv. 

CO2  Pressure 

PH  of  blood 

PH  of  blood  at 

mm.  Hg. 

at  40  mm.  CO2 

existing  alveolar 

pressure 

CO2  pressure 

Meat  Diet 

38.9 

7-33 

7-34 

Vegetable  Diet 

43-3 

7.42 

7.36 

It  will  be  seen  that  at  40  mm.  CO2  pressure  the  blood  sample 
taken  with  the  meat  diet  was  distinctly  more  acid  than  with  the 
vegetable*  diet,  but  that  at  the  existing  alveolar  CO2  pressure  the 
two  values  for  PH  were  identical,  at  least  within  the  limit  of  ac- 
curacy of  the  method  of  measurement.  Hence  the  respiratory 
center  had  regulated  the  alveolar  CO2  pressure  in  such  a  manner 
as  to  keep  the  PH  of  the  blood  almost  constant. 

There  is  other  evidence  pointing  in  the  same  direction.  Barcroft 
found  that  on  the  Peak  of  Teneriffe  the  dissociation  curve  of 
human  blood  appeared  to  be  normal,  provided  that  the  curve 
was  investigated,  not  at  the  normal  sea  level  alveolar  CO2  pressure 
of  about  40  mm.,  but  at  the  existing  resting  alveolar  CO2  pres- 
sure.22 We  got  a  similar  result  at  a  greater  height  on  Pike's 
Peak,23  as  did  also  Barcroft  and  his  co-workers  on  Monte  Rosa.24 

21  Hasselbalch,  Btochem.  Zeitschr.,  XLVI,  p.  416,  1912. 

22  Barcroft,  Journ.  of  Physiol.,  XLII,  p.  44,  1911. 

23  Douglas,  Haldane,   Henderson,  and  Schneider,  Phil.   Trans.  Roy.  Soc.,   (B) 
203,  p.  201,  1913- 

24  See  Chapter  XVII,  of  Barcroft,  The  Respiratory  Function  of  the  Blood,  1913. 


1 84  RESPIRATION 

As  already  pointed  out  this  curve  is  shifted  to  the  right  or  left  with 
varying  alkalinity,  and  the  shifting  is  a  moderately  delicate  index 
of  the  variation  (Chapter  III).  Peters,25  working  with  Barcroft, 
has  shown  that  the  shifting  with  variations  in  CO2  pressure  de- 
pends on  the  shifting  of  PH.  Hence  the  constancy  of  the  dissocia- 
tion curve  appeared  to  be  a  direct  index  of  the  constancy  in  PH  of 
the  blood.  The  lowering  of  alveolar  CO2  pressure  at  high  altitudes 
seemed  therefore  to  be  just  sufficient  to  keep  the  PH  of  the  blood 
steady  in  so  far  as  direct  methods  enable  us  to  measure  the  degree 
of  steadiness.  As  will  be  seen  below,  however,  there  is  physio- 
logical evidence  that  the  blood  is  actually  more  alkaline  at  high 
altitudes.  More  recently  Hasselbalch  and  Lindhard  have  made 
direct  electrometric  measurement  of  PH  in  a  steel  chamber  after 
exposure  of  sufficient  duration  to  the  low  pressure,  and  their 
measurements  give  practically  the  same  result.26  The  resting  al- 
veolar CO2  pressure  on  Pike's  Peak  was  about  27  mm.,  or  13  mm. 
below  that  at  sea  level.  Raising  the  alveolar  CO2  pressure  on  Pike's 
Peak  to  40  mm.  would  have  caused  the  extremest  panting. 

As  soon  as  the  results  of  Hasselbalch  and  Lundsgaard  were 
published,  it  was  possible  to  estimate  quantitatively  the  delicacy 
with  which  the  respiratory  center  responds  to  variations  in  the 
reaction  of  the  blood  :  for  the  delicacy  of  the  reaction  of  the  center 
to  variations  of  CO2  pressure  was  known  from  our  previous  ex- 
periments, while  the  curves  of  Hasselbalch  and  Lundsgaard  made 
it  possible  to  convert  variations  of  CO2  pressure  into  variations  of 
PH  in  the  blood.  Some  confusion  arose,  however,  owing  to  the 
fact  that  Lindhard,27  and  Hasselbalch  and  Lindhard,28  had  mean- 
while published  experiments  which  seemed  to  indicate  that  the 
respiratory  center  in  man  is  commonly  far  less  sensitive  to  CO2 
than  Priestley  and  I  had  found.  The  matter  was  therefore  rein- 
vestigated  by  Campbell,  Douglas,  Hobson,  and  myself.29  We 
found  that  the  Danish  observers  had  been  deceived,  owing  to  a 
faulty  modification  of  the  method  of  sampling  the  alveolar  air. 
The  fresh  experiments  gave  practically  the  same  results  as  Priest- 
ley and  I  had  obtained,  so  we  could  make  the  calculation  accord- 
ingly. 

A  rise  of  0.2  per  cent  or  1.5  mm.  in  the  CO2  pressure  of  the 

"Barcroft,  The  Respiratory  Function  of  the  Blood,  p.  316,  1913. 

28  Hasselbalch  and  Lindhard,  Biochem.  Zeitschr.,  68,  p.  293,  1915. 

87  Lindhard,  Journ.  of  Physiol.,  XLII,  p.  337,  1911. 

88  Hasselbalch  and  Lindhard,  Skand.  Arch.  f.  Physiol.,  XXVIII,   1911. 

29  Campbell,  Douglas,  Haldane,  and  Hobson,  Journ.  of  Physiol.,  XLVI,  p.  301, 
1913- 


RESPIRATION  185 

alveolar  air  and  arterial  blood  causes  an  increase  of  about  100  per 
cent  in  the  resting  alveolar  ventilation,  and  from  Figure  54  it 
will  be  seen  that  this  corresponds  to  a  difference  of  .012  in  PH. 
This  difference,  large  as  its  physiological  effect  is,  cannot  be  de- 
tected with  certainty  by  the  electrometric  method,  or  by  indicators, 
and  is  quite  undetectable  by  the  shifting  of  the  dissociation  curve 
of  oxyhaemoglobin.  Nevertheless  a  twentieth  of  this  difference 
would  produce  an  easily  measurable  effect  on  the  breathing  or 
alveolar  CO2  pressure.  The  astounding  delicacy  of  the  regulation 
of  blood  reaction  is  thus  evident.  No  existing  physical  or  chemical 
method  of  discriminating  differences  in  reaction  approaches  in 
delicacy  the  physiological  reaction.  Unfortunately,  however,  the 
quantitative  significance  of  our  calculation  has  not  yet  been  ap- 
preciated. The  blood  within  the  living  body  is  still  treated  as  if 
its  reaction  were  not  only  variable,  during  rest,  as  it  is,  but  capable 
of  showing  the  variations  by  the  existing  very  rough  chemical  and 
physical  reactions.  One  might  as  well  try  to  cut  delicate  histo- 
logical  sections  with  a  blunt  carving  knife,  as  try  to  demonstrate 
ordinary  very  minute  changes  in  blood  reaction  by  the  existing 
physical  and  chemical  methods. 

It  was  discovered  by  Christiansen,  Douglas,  and  myself,  as 
previously  set  forth,  that  the  reduction  of  oxyhaemoglobin,  as 
this  occurs  in  the  course  of  the  circulation,  has  an  effect  re- 
sembling that  of  the  addition  of  alkali  to  the  blood.  Thus  the 
CO2  pressure  of  the  blood  in  the  systemic  capillaries  is  pre- 
vented from  rising  nearly  as  high  as  it  would  otherwise  do.  The 
hydrogen  ion  concentration  of  the  blood  is  also  prevented  from 
rising  in  correspondence  with  the  actual  greatly  restricted  increase 
in  CO2  pressure.  Accordingly  the  actual  increase  of  hydrogen  ion 
concentration  in  mixed  venous  as  compared  with  arterial  blood 
must  be  very  small.  In  this  way  the  extraordinarily  delicate  regu- 
lation of  the  reaction  of  arterial  blood  becomes  much  more  intelli- 
gible, as  venous  blood  must  be  very  little  less  alkaline  than  arterial 
blood.  In  determining  the  hydrogen  ion  concentration  of  blood  by 
the  ordinary  electrometrical  method  it  is  necessary  to  reduce  the 
blood  first,  as  the  presence  of  oxygen  interferes  with  the  action  of 
the  hydrogen  electrode.30  Thus  the  determination  is  made  on  re- 
duced, or  by  Barcroft's  method  on  partially  reduced,  blood,  but 
with  a  CO2  pressure  corresponding  to  that  of  arterial  blood.  It  is 

80  Peters,  Journ.  of  Physiol.,  48,  Proc.  Phys.  Soc.,  p.  vii,  1914.  It  is  probable 
that  owing  to  incomplete  reduction  the  values  obtained  by  Hasselbalch  have  been 
slightly  too  low. 


1 86 


RESPIRATION 


evident,  therefore,  that  the  value  obtained  for  the  hydrogen  ion 
concentration  is  lower  than  that  which  exists  in  either  arterial  or 
venous  blood  in  the  living  body.  To  investigate  the  amount  of  this 
difference  Parsons31  adopted  the  method  of  determining  the  hy- 
drogen ion  concentration,  not  in  whole  blood,  but  in  its  serum,  of 
which  the  hydrogen  ion  concentration  is  not  altered  when  free 
oxygen  is  removed.  Using  this  method,  he  found  that  with  normal 
blood  the  PH  at  a  constant  pressure  of  CO2  at  anywhere  near  the 
alveolar  CO2  pressure  is  greater  by  .038  in  the  oxygenated  than 
the  reduced  blood.  Figure  55  shows  his  results.  From  them  and 


8.6. 
6-5 

8-4 
83 
8.2 
81 

e-o 

79 
78 
77 
76 
75 
74 
73 

72 
7/ 


\ 


\ 


MM.  HG 


o 


10 


20 


30 


40 


50 


60 


70 


80 


Figure  55. 

Curve  R,  completely  reduced  blood.  Curve  O,  fully  oxygenated 
blood.  X,  direct  measurements  on  reduced  blood  without  removal  of 
corpuscles.  H,  Hasselbalch's  curve. 

from  Figure  26  (Chapter  V)  it  is  possible  to  calculate  what 
the  difference  for  normal  blood  between  the  PH  of  arterial  and 
mixed  venous  blood  is,  assuming  that  the  venous  blood  has  lost 
a  certain  proportion  of  its  oxygen  and  simply  gained  a  corre- 
sponding proportion  of  CO2.  If  the  venous  blood  had  lost  all  its 

"Parsons,  Journ.  of  Physwl.,  LI,  p.  440,   1917. 


RESPIRATION 


oxygen  the  difference  would  be  .07,  as  shown  in  Figure  56  from 
Parsons's  paper.  Assuming,  however,  that  the  mixed  venous  blood 
loses  normally  a  fourth  of  its  combined  oxygen  (see  Chapter  X), 
the  difference  is  only  .0175 — a  difference  which  can  hardly  be 
detected  except  by  physiological  methods,  and  which  corresponds 
to  a  rise  of  only  0.3  per  cent  in  the  alveolar  CO2  percentage. 

It  might  be  supposed  that  in  order  to  obtain  the  true  PH  of 
arterial  blood  under  abnormal  conditions  all  that  is  necessary  is  to 
add  a  constant  to  the  value  obtained  for  reduced  blood;  and  that 
consequently  the  ordinary  methods  of  determining  PH  (whether 
electrometrically  or  from  indications  given  by  the  dissociation 


7-6 


7-5 


7-3 


7-2 


1-1 


40  50 60  70 

TOTAL  C0t  CONT£NT(c.c/iQocJ  OF  BLOOD 

Figure  56. 

The  slope  of  the  line  AC  shows  the  rate  at  which  the  PH 
of  blood  increases  as  its  content  of  CO2  increases  in  the 
capillaries. 

curve  of  oxyhaemoglobin)  give  reliable  indications  of  any  altera- 
tion in  the  PH  of  the  arterial  blood.  There  is,  however,  no  evidence 
at  present  that  this  is  the  case,  and  there  is  in  fact  other  evidence 
pointing  in  the  opposite  direction. 

If,  in  the  first  place,  the  proportion  of  haemoglobin  in  the  blood 
is  altered,  there  will  presumably  be  an  alteration  in  the  difference 
between  the  PH  of  fully  oxygenated  and  of  reduced  blood.  Apart 
altogether  from  this,  however,  there  may  be  another  kind  of  al- 
teration in  this  difference.  In  the  paper  by  Christiansen,  Douglas, 
and  myself,  it  was  pointed  out  that  the  probable  reason  why  re- 
duced blood  appears  to  be  more  alkaline  than  oxygenated  blood 
is  that  on  reduction  the  haemoglobin  becomes  more  aggregated 
and  therefore  acts  less  strongly  as  an  acid.  In  abnormal  blood  the 
degree  of  increased  aggregation  may  be  either  increased  or  di- 
minished. This  will  alter  the  difference  in  PH  between  oxygenated 
and  reduced  blood,  and  will  also,  if  our  theory  as  to  the  cause  of 


1 88  RESPIRATION 

the  peculiar  shape  of  the  dissociation  curve  of  the  oxyhaemoglobin 
in  blood  is  correct,  alter  the  shape  of  the  dissociation  curve. 

In  a  quite  recent  paper  Lovatt  Evans32  has  shown  that  the  PH 
of  blood  as  determined  colorimetrically  by  an  indicator  method 
is  as  much  as  0.2  higher  than  when  determined  electrometrically. 
He  has  also  shown  pretty  conclusively  that  the  electrometric 
method  has  an  error  owing  to  the  formation  of  formate  from 
carbonate  by  catalytic  action  at  the  electrode,  so  that  the  PH  of 
blood  is  higher  by  0.2  than  appears  from  the  electrometric  de- 
terminations. The  new  colorimetric  method  of  Dale  and  Evans33 
seems  to  avoid  several  defects  inherent  in  the  electrometric  method 
as  applied  to  blood. 

On  the  existing  evidence,  and  allowing  for  mistaken  inferences 
which  have  been  drawn  in  ignorance  of  the  peculiar  properties  of 
haemoglobin  (as  it  exists  in  the  red  corpuscles)  in  regulating  the 
PH  of  blood,  it  seems  evident  that  during  health  the  regulation 
of  the  reaction  of  the  arterial  blood  is  carried  out  with  a  delicacy 
and  constancy  of  which  we  can  at  present  only  obtain  a  real  con- 
ception by  physiological  observations.  The  foregoing  discussions 
show  that  there  are  at  least  three  regulators  of  the  reaction — the 
lungs,  the  kidneys,  and  the  liver.  We  can  also  now  form  a  general 
conception  of  how  these  regulators  act  under  ordinary  conditions. 

The  part  played  by  the  lungs  in  this  regulation  is,  quite  clearly, 
to  deal  rapidly  with  variations  in  reaction  due  to  varying  pro- 
duction of  CO2,  and  particularly  to  the  rapid  variation  caused  by 
varying  muscular  exertion.  By  keeping  the  alveolar  CO2  pressure 
approximately  normal,  the  action  of  the  lungs  keeps  the  arterial 
CO2  pressure  approximately  normal;  and  so  long  as  the  dissocia- 
tion curve  for  CO2  in  the  blood  is  also  kept  normal  by  other  means 
the  reaction  of  the  arterial  blood  is  also  kept  almost  exactly 
normal.  If,  however,  owing  to  rapid  production  of  lactic  acid  in 
muscles,  rapid  secretion  of  gastric  or  pancreatic  juice,  or  other 
causes,  the  dissociation  curve  for  CO2  is  temporarily  disturbed,  the 
breathing  compensates  approximately  at  once  for  the  disturbance 
in  blood  reaction. 

The  part  played  by  the  kidneys  seems  also  clear.  They  not  only 
respond  to  the  minutest  variations  in  blood  alkalinity  by  secreting 
more  acid  or  more  alkaline  urine,  but  also  tend  to  keep  normal  the 
proportion  of  soda  and  potash  and  other  crystalloid  substances 
existing  in  the  blood.  In  this  way  the  dissociation  curve  of  the  CO2 

"Lovatt  Evans,  Journ.  of  Physiol.,  LIV,  p.  353,  1921. 
"Dale  and  Evans,  Journ.  of  Physiol,,  LIV,  p.  167,  1920. 


RESPIRATION  189 

in  blood  is  kept  normal ;  and  no  physiological  phenomenon  is  more 
striking  than  the  constancy  of  this  curve  under  normal  conditions. 
If  the  proportion  of  available  alkali  is  temporarily  diminished 
by  acid  poured  out  into  the  blood,  the  kidneys  help  to  restore  it 
to  normal  again ;  and  similarly  with  excess  of  alkali.  The  action 
of  the  kidneys  is  slow  compared  with  that  of  the  lungs;  but  is 
apparently  still  more  delicate.  As  L.  J.  Henderson  was  the  first  to 
point  out  clearly34  the  PH  of  urine  is  no  measure  of  the  total  acid 
excreted  in  it,  since  urine,  like  blood,  contains  buffer  substances. 
Among  these  phosphoric  acid  plays  the  main  part  in  acid  urine, 
and  carbonic  acid  in  alkaline  urine.  To  measure  the  acid  excreted 
titration  must  be  employed,  and  in  titrating  alkaline  urine  the 
combining  CO2  must  be  allowed  to  escape.33 

The  part  played  by  the  liver  is  to  neutralize  as  far  as  possible 
the  disturbing  effect  of  any  excess  of  acid  or  of  alkali  introduced 
into  the  body  through  the  intestines,  or  formed  in  the  tissues.  By 
allowing  more,  or  less,  ammonia  to  enter  the  circulation  the 
liver  regulates  the  reaction  of  the  blood ;  and  the  neutral  ammonia 
salts  are  afterwards  eliminated  by  the  kidneys  as  being  foreign 
substances.  The  importance  of  the  part  played  by  the  liver  under 
normal  conditions  is  evident  enough  in  view  of  the  fact  that  in 
man  the  ammonia  excreted  daily  would  just  about  suffice  to  neu- 
tralize all  the  sulphuric  acid  formed  daily.  Like  that  of  the  kid- 
neys, the  action  of  the  liver  is  slow  and  delicate  as  compared  with 
that  of  the  lungs. 

Possibly  the  intestines  also  play  an  active  part  in  regulating 
the  blood  reaction.  It  is  known,  at  any  rate,  that  alkali  may  be 
eliminated  from  them  in  the  form  of  insoluble  alkaline  phosphates. 

We  have  now  to  consider  how  this  joint  regulation  behaves 
when  the  action  of  one  of  the  regulators  is  interfered  with;  and 
the  case  of  interference  with  the  lung  regulation  will  be  considered 
first.  This  regulation  may  be  disturbed  in  various  ways,  but  per- 
haps most  is  known  at  present  as  to  its  disturbance  owing  to  the 
fact  that  under  abnormal  conditions  the  stimulus  of  anoxaemia  in- 
creases the  breathing,  and  thus  disturbs  the  normal  relation  be- 
tween the  lung  ventilation  and  the  degree  of  stimulus  of  the 
respiratory  center  owing  to  varying  reaction  of  the  arterial  blood. 
The  history  of  the  development  of  knowledge  on  this  point  is  very 
instructive. 

84  L.  J.  Henderson,  Amer.  Journ.  of  Physiol.,  21,  p.  427,  1908. 
86Davies,   J.  B.   S.  Haldane,  and  Kennaway,  Journ.   of  Physiol.,  LIV,  p.   32, 
1920. 


190 


RESPIRATION 


It  has  already  been  shown  in  Chapters  VI  and  VII  that  until 
the  oxygen  pressure  of  the  inspired  air  is  lowered  by  about  a  third, 
or  that  of  the  alveolar  air  to  about  half  (i.e.,  from  about  100  mm. 
to  50  mm.)  there  is  no  marked  immediate  increase  in  the  breath- 
ing. The  effect  on  the  respiratory  center  of  the  very  distinct  degree 


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Atmospheric  pressure  in  mm.  of  mercury. 

Figure  57. 
Alveolar  gas  pressures  in  relation  to  barometric  pressure  or  altitude. 

of  anoxaemia  which  is  undoubtedly  produced,  in  the  manner  ex- 
plained in  Chapter  VII,  is  almost  entirely  masked  by  the  con- 
trary effect  due  to  extra  washing  out  of  CO2  and  consequent 
lowering  of  the  PH  in  the  arterial  blood.  But  if  exposure  to  the 
lowered  oxygen  pressure  is  continued,  not  merely  for  perhaps  an 
hour,  but  for  days  or  weeks,  there  is  a  quite  marked  increase  in 


RESPIRATION  191 

the  breathing,  as  shown  by  a  fall  in  the  alveolar  CO2  pressure. 
This  fact,  already  referred  to  in  connection  with  the  historical 
development  of  the  theory  of  regulation  of  the  breathing  by  the 
blood  reaction,  was  brought  out  in  full  clearness  by  the  investiga- 
tions carried  out  in  connection  with  the  Pike's  Peak  expedition 
by  Miss  FitzGerald  on  persons  fully  acclimatized  at  different 
altitudes.36  Figure  57  represents  graphically  her  results  on  this 
subject.  It  will  be  seen  that  in  such  persons  the  alveolar  CO2  pres- 
sure falls  regularly  with  increase  of  altitude.  In  other  words  the 
breathing  increases  in  a  regular  ratio  with  diminution  in  the  oxy- 
gen pressure  of  the  inspired  air. 

What  is  the  cause  of  this  increase?  Since  the  experiments, 
already  referred  to,  of  Boycott,  Ogier  Ward,  and  myself,  it  has 
been  pretty  generally  assumed  that  in  response  to  the  stimulus  of 
anoxaemia  a  slight  acidosis,  sufficient  to  account  for  the  increased 
breathing,  develops  in  the  blood.  This  explanation  received  strong 
confirmation  from  the  discovery  by  Barcroft  in  the  Teneriffe 
experiments  that  the  dissociation  curve  of  the  oxyhaemoglobin  of 
the  blood  at  high  altitudes  is  sensibly  the  same  in  presence  of  the 
existing  alveolar  CO2  pressure  as  at  sea  level  in  presence  of  the 
alveolar  CO2  pressure  existing  there.  The  extra  acid,  or  dimin- 
ished available  alkali,  present  in  the  blood  seemed  just  to  compen- 
sate for  what  would  otherwise  be  increased  alkalinity  due  to  the 
lowered  CO2  pressure.  The  physiological  facts,  however,  do  not 
correspond  with  the  lactic  acid  theory.  Moreover  no  excess  of 
lactic  acid  could  be  discovered  by  Ryffel  in  the  urine  and  hardly 
any  in  the  blood,  of  persons  exposed  to  low  pressures  in  a  respira- 
tion chamber  or  steel  chamber,37  or  indeed  in  persons  at  high 
altitudes  ;38  and  no  other  abnormal  acid  could  be  discovered  in  the 
blood.  Hence  the  theory  of  an  acidosis  due  to  formation  of  ab- 
normal acids  cannot  be  substantiated.  In  the  report  of  the  Pike's 
Peak  Expedition  we  adopted  the  theory  that  the  anoxaemia  alters 
the  activity  of  the  kidneys  in  such  a  way  that  they  regulate  the 
blood  to  a  lower  level  of  alkalinity. 

Another,  and  essentially  similar,  theory  was  adopted  by  Has- 
selbalch  and  Lindhard  as  the  result  of  experiments  in  a  steel 
chamber.39  They  found  that  the  excretion  of  ammonia  is  markedly 

"FitzGerald,  Phil.  Trans.  Roy.  Soc.,  203  (B),  p.  351,  1913;  and  Proc.  Roy. 
Soc.,  88  (B),  p.  248,  1914.  See  also,  Yandell  Henderson,  Journ.  of  Biol.  Chem., 
1920. 

"Ryffel,  Journ.  of  Physiol.,  XXXIX  (Proc.  Physiol.  Soc.),  p.  xxix,  1910. 

88  See  Barcroft,  The  Respiratory  Function  of  the  Blood,  p.  260. 

"Hasselbalch  and  Lindhard,  Biochem.  Zeitschr.,  68,  p.  295,  1915. 


1 92  RESPIRATION 

diminished  at  the  lowered  pressure,  and  were  thus  led  to  the  theory 
that  the  acidosis  of  high  altitudes  is  due  to  diminished  formation 
of  ammonia  by  the  liver  as  a  consequence  of  anoxaemia. 

The  question  was  again  taken  up  in  a  series  of  experiments  in 
steel  chambers  by  Kellas,  Kennaway,  and  myself,  in  which  care- 
ful measurements  were  made  of  the  excretion  of  acid  and  am- 
monia.40 We  found  that  even  with  a  comparatively  slight  diminu- 
tion of  pressure  there  was  a  great  diminution  in  the  excretion  of 
acid  and  ammonia,  and  the  urine  passed  to  the  alkaline  side  of 
neutrality.  The  true  explanation  of  the  supposed  acidosis  then 
revealed  itself  to  us.  The  kidneys  and  liver  were  responding  quite 
normally,  but  to  an  alkalosis,  this  alkalosis  being  produced  by  the 
increase  (largely  masked)  of  breathing  caused  by  the  anoxaemia. 
A  similar  view  of  the  supposed  acidosis  of  high  altitudes  was 
reached,  on  independent  grounds  which  will  be  discussed  below, 
by  Yandell  Henderson.41 

The  increased  excretion  of  alkali  and  diminished  formation  of 
ammonia  lead  gradually  towards  a  compensation  of  the  alkalosis 
and  simultaneous  relief  of  the  anoxaemia,  this  relief  being  due  to 
the  increased  oxygen  supply  to  the  lung  alveoli,  and  to  other 
causes  discussed  in  Chapters  IX  and  X.  But  the  final  result  is  a 
compromise.  A  certain  small  degree  of  anoxaemia  and  consequent 
alkalosis  still  remains,  as  evidenced  by  a  continued  low  excretion 
of  ammonia  and  other  physiological  symptoms  and  by  the  fact 
that  on  removal  of  the  anoxaemia  there  is  a  quite  appreciable 
immediate  rise  in  the  alveolar  CO2  pressure,  as  was  shown  for 
instance,  when  we  breathed  air  enriched  with  oxygen  after  we  had 
become  acclimatized  on  Pike's  Peak.  The  extra  excretion  of  alkali 
comes  to  an  end,  however,  as  the  kidneys  cannot  reduce  the  blood 
alkali  further  without  very  serious  alteration  of  the  normal  balance 
of  salts  in  the  blood. 

The  supposed  acidosis  is  thus  not  an  acidosis  at  all,  but  the  in- 
complete compensation  of  an  alkalosis.  The  "adaptation"  of  the 
blood  so  as  to  relieve  the  alkalosis  and  anoxaemia  is  also  nothing 
but  an  extension  of  the  everyday  adaptations  by  which  alkalosis 
and  anoxaemia  are  continuously  being  prevented.  The  reason  why 
the  adaptation  takes  so  long  at  low  atmospheric  pressures  is  simply 
that  it  takes  a  long  time  for  the  kidneys  and  liver  to  get  level  with 
the  very  prolonged  and  considerable  work  thrown  on  them  by 

40  Kellas,  Kennaway,  and  Haldane,  Journ.  of  Physwl.,  LIII,  p.  181,  1919. 

41  Yandell  Henderson,  Science  (N.  S.),  XLIX,  p.  431,  1910;  see  also  the  series 
of  papers  by  Henderson  and  Haggard,  Journ.  of  Biol.  Chem.,  1919-1921  incl. 


RESPIRATION  193 

progressive  increase  in  the  breathing.  They  are,  as  it  were,  pursu- 
ing in  a  leisurely  manner  a  goal  which  is  constantly  receding  from 
them,  so  that  it  is  a  long  time  before  they  finally  reach  it.  The 
quantity  of  alkali  which  has  to  be  removed  from  the  blood  and 
tissues  is  very  large,  as  a  simple  calculation  will  show. 

With  the  compensation  of  the  alkalosis  there  also  comes  com- 
pensation of  any  secondary  anoxaemia  caused  by  the  alkalosis  as 
a  consequence  of  the  Bohr  effect  discussed  so  fully  in  Chapters  IV 
and  VI.  Owing  to  the  increased  breathing  the  percentage  satu- 
ration of  the  arterial  blood  is  (without  any  allowance  for  increased 
oxygen  secretion)  as  high  as  at  first,  while  the  oxygen  pressure  in 
the  systemic  capillaries  is  higher  (i.e.,  nearer  normal)  on  account 
of  the  decreased  alkalosis.  Cyanosis  may  be,  however,  quite  as 
marked  as  before.  By  the  administration  of  acid  the  adaptation 
to  a  lowered  oxygenation  of  the  arterial  blood  could  doubtless 
be  hastened. 

The  study  of  responses  to  the  anoxaemia  and  alkalosis  of  high 
altitudes  is  of  great  medical  interest,  since,  as  already  explained 
in  the  two  preceding  chapters,  anoxaemia  is  a  very  common  and 
often  extremely  dangerous  clinical  condition.  There  can  be  no 
doubt  that  the  same  responses  as  occur  in  healthy  persons  at 
high  altitudes  occur  also  in  patients  suffering  from  anoxaemia.  It 
is  therefore  important  not  to  misunderstand  these  responses. 
During  the  war,  for  instance,  the  intensely  dangerous  anoxaemia 
of  acute  gas  poisoning  and  "shock"  was  sometimes  treated  by  the 
administration  of  alkalies,  on  the  theory,  based  on  nothing  but  the 
unintelligent  use  of  a  new  method  of  blood  examination,  that  the 
patients  were  suffering  from  "acidosis."  Physiological  knowledge 
as  to  the  deadly  significance  of  serious  anoxaemia,  and  the  (sup- 
posed) acidosis  as  an  adaptive  change  tending  towards  its  com- 
pensation, was  ignored.  It  is  also  important  to  understand  that  the 
adaptive  changes  require  time,  and  that  so-called  palliative  treat- 
ment, by  giving  this  time,  may  in  reality  be  curative. 

Another  cause  of  interference  with  the  lung  regulation  of  blood 
reaction  is  to  place  an  animal  or  man  in  an  atmosphere  in  which 
the  percentage  or  pressure  of  CO2  is  so  high  that  the  regulation 
breaks  down  completely  and  there  is  in  consequence  an  excessive 
and  lasting  fall  in  the  PH  of  the  blood.  This  condition  was  studied 
recently  in  animals  by  Yandell  Henderson  and  Haggard.42  They 
made  the  very  important  and  significant  discovery  that  the  acido- 

**  Yandell  Henderson  and  Haggard,  Journ.  of  Biol.  Chem.,  XXXIII,  p.  333, 
1918. 


I94  RESPIRATION 

sis  thus  produced  gradually  brings  about  a  marked  increase  in  the 
capacity  of  the  blood  for  combining  with  CO2.  In  other  words  the 
dissociation  curve  of  the  CO2  in  blood,  if  plotted  as  in  Figure  25, 
would  occupy  a  higher  position.  This  is  evidently  a  change  tending 
to  counteract  the  diminished  blood  alkalinity  produced  by  the 
excess  of  CO2. 

The  same  observers  found  that  on  prolonged  and  forced  arti- 
ficial ventilation  of  the  lungs,  so  as  to  produce  a  condition  of  al- 
kalosis,  there  is  a  corresponding  diminution  in  the  capacity  of  the 
blood  for  combining  with  CO2.  This  is  also  a  change  towards 
the  normal  alkalinity.  Thus  in  an  alkalosis  produced  by  excessive 
removal  of  CO2  the  available  alkali  in  the  blood  diminished,  while 
in  an  acidosis  produced  by  excess  of  CO2  the  available  alkali 
increased.  It  is  clear  that  in  either  case  the  change  is  of  a  character 
tending  to  neutralize  the  change  in  blood  reaction. 

What  is  the  significance  of  this  change?  It  occurs  much  too 
quickly  to  be  capable  of  explanation  as  due  to  an  adaptive  re- 
sponse by  the  kidneys  and  liver.  The  probability  is,  therefore,  that 
it  is  due  to  exchange  of  anions  between  the  tissues  and  blood  in 
the  manner  discussed  in  Chapter  IV  (Addendum),  and  is  indica- 
tive, therefore,  of  very  severe  alkalosis  or  acidosis  of  the  tissues. 
This  would  help  to  account  for  the  very  dangerous  symptoms 
which  Henderson  and  Haggard  found  to  be  an  accompaniment  of 
any  considerable  diminution  of  the  available  alkali  of  the  blood, 
when  the  diminution  was  produced  by  excessive  artificial  respira- 
tion. Thus  a  diminution  of  about  40  per  cent  in  the  capacity  of 
the  blood  for  combining  with  CO2  was  fatal  to  the  animal.  A 
similar  diminution  due  to  the  acidosis  caused  by  running  quickly 
up  a  stair  is  hardly  felt  at  all.  In  the  latter  case  the  diminution  in 
available  alkali  in  the  blood  indicates  a  quite  trifling  acidosis, 
while  in  the  former  a  similar  change  in  the  blood  indicates  a 
severe  and  fatal  alkalosis. 

These  and  other  experiments43  of  these  investigators  brought 
out  in  a  striking  manner  that  it  is  a  complete  mistake  to  regard 
diminution  of  the  available  alkali  (or  so-called  "alkaline  reserve") 
of  the  blood  as  a  definite  sign  of  acidosis  in  the  living  body.  The 
"alkaline  reserve"  of  the  blood  and  whole  body  is  only  another 
name  for  its  "titration  alkalinity" ;  and  it  has  already  been  shown 
above  that  titration  alkalinity  is  no  measure,  and  not  even  a  sure 
qualitative  indication,  of  the  real  alkalinity  of  the  blood.  In  the 

43  Haggard  and  Henderson,  Journ.  of  Bwl.  Chem.,  XXXIX,  p.  163,  1919; 
and  XLIII,  pp.  3,  15,  and  29,  1920. 


RESPIRATION  195 

experiments  of  Yandell  Henderson  and  Haggard  the  animals  were 
suffering  from  severe  alkalosis  although  the  "alkaline  reserve^  or 
titration  alkalinity  of  their  blood  was  greatly  diminished;  and 
similarly  they  were  suffering  from  severe  acidosis  although  the 
"alkaline  reserve"  of  their  blood  was  greatly  increased. 

It  was  these  observations  that  led  Yandell  Henderson  to  the 
same  conclusion  which  we  reached — namely,  that  in  the  anoxae- 
mia of  high  altitudes  there  is  a  condition  of  alkalosis,  and  not  of 
acidosis,  in  spite  of  the  greatly  reduced  titration  alkalinity  or 
"alkaline  reserve"  of  the  blood. 

A  ready  method  of  interfering  temporarily  with  the  regulation 
of  blood  reaction  by  the  lungs  is  forced  breathing.  This  can  be 
continued  for  a  considerable  time  if  it  is  employed  in  moderation. 
Leathes44  found  that  if  forced  breathing  is  continued  for  some 
time  the  urine  becomes  alkaline  to  litmus,  and  the  titration  alka- 
linity has  still  more  recently  been  investigated  by  Davies,  J.  B.  S. 
Haldane,  and  Kennaway.45  The  titration  alkalinity  is,  however, 
not  so  striking  as  after  a  large  dose  of  sodium  bicarbonate  has  been 
taken.  The  same  observers  found  that  after  a  large  dose  of  sodium 
bicarbonate  there  was  not  only  a  rise  of  as  much  as  I  per  cent  in  the 
alveolar  CO2  pressure  for  some  hours,  but  the  available  alkali  in 
the  blood  (as  shown  by  the  dissociation  curve  for  CO2)  was 
markedly  increased,  while  there  was  also  a  great  increase  in  the 
titration  alkalinity  of  the  urine.  Large  quantities  of  bicarbonate 
(readily  determined  by  the  blood-gas  apparatus)  were  present  in 
the  urine,  which  effervesced  briskly  on  the  addition  of  acid,  though 
the  actual  alkalinity  of  the  urine  was  of  course  only  feeble,  since 
the  CO2  acted  as  a  buffer.  The  titration  alkalinity  (after  removal 
of  liberated  CO2)  was  equivalent  to  nearly  I  per  cent  of  HC1.  The 
ammonia  had  completely  disappeared  from  the  urine,  and  this 
was  also  the  case  after  forced  breathing,  although  such  a  degree 
of  forced  breathing  as  was  practicable  did  not  appreciably  dimin- 
ish the  available  alkali  in  the  blood  within  one  and  one-half 
hours.  A  stay  of  several  hours  in  air  containing  5  to  6  per  cent  of 
CO2  was  also  not  sufficient  to  increase  appreciably  the  available 
alkali  of  the  blood,  although  the  titration  acidity  of  the  urine  was 
increased,  along  with  increased  excretion  of  ammonia.  Collip  has, 
however,  found  that,  as  might  be  expected  from  the  change  in 
distribution  of  acid  and  alkali  between  plasma  and  corpuscles 

"Leathes,  Brit.  Med.  Journ.,  Aug.  9,  1919. 

46  Davies,  J.  B.  S.  Haldane,  and  Kennaway,  Journ.  of  Physiol.,  LIV,  p.  32, 
1920. 


196  RESPIRATION 

when  the  PH  of  blood  is  altered,  the  alkaline  reserve  of  the  plasma 
was  distinctly  diminished  by  forced  breathing.46 

The  blood  reaction  may,  of  course,  be  disturbed  in  other  ways 
than  by  interference  with  respiration.  One  of  these  ways  is  by 
ingestion  of  acids  or  by  production  within  the  body  of  great  ex- 
cess of  some  organic  acid.  Walter's  experiments,  interpreted  in 
the  light  of  our  present  knowledge,  showed  the  effects  of  acid 
poisoning  in  stimulating  to  the  utmost  all  the  means  of  diminishing 
acidosis,  including  excessive  breathing,  greatly  increased  forma- 
tion of  ammonia,  and  secretion,  presumably,  of  an  abnormally 
acid  urine.  The  titration  alkalinity  or  "alkaline  reserve"  of  the 
blood  and  doubtless  also  of  the  whole  body  was  evidently  dimin- 
ished very  greatly. 

Christiansen,  Douglas,  and  Haldane  produced  a  temporary  true 
acidosis  by  flooding  the  blood  with  lactic  acid  produced  by  mus- 
cular anoxaemia  during  the  heavy  exertion  of  running  several 
times  upstairs.  In  this  case  two  results  followed.  In  the  first  place 
there  was  a  fall  in  the  resting  alveolar  CO2  pressure,  which  was, 
in  several  experiments,  about  39  mm.  before  the  exertion,  and 
30.5  mm.  about  10  minutes  after  the  exertion.  The  blood  absorbed 
about  49  volumes  of  CO2  per  100  of  blood  before  the  exertion  in 
presence  of  the  existing  alveolar  CO2  pressure,  and  only  about 
28  afterwards.  After  one  and  one-half  hours  both  the  resting 
alveolar  CO2  pressure  and  the  absorbing  power  of  the  blood  for 
CO2  had  returned  to  normal. 

In  these  experiments  the  capacity  of  the  blood  for  absorbing 
CO2  at  a  CO2  pressure  of  40  mm.  had  been  reduced  by  about  40 
per  cent,  and  the  resting  alveolar  CO2  pressure  by  about  20  per 
cent,  corresponding  to  an  increase  of  about  25  per  cent  in  the 
lung  ventilation.  There  was  thus  a  very  distinct  acidosis ;  but  ref- 
erence to  the  calculations  already  made  will  show  that  the  acidosis 
could  not  have  been  detected  by  any  existing  method  of  directly 
estimating  hydrogen  ion  concentration. 

The  great  drop  in  the  capacity  of  the  blood  for  combining  with 
CO2  suggests  at  first  that  the  blood  had  become  correspondingly 
inefficient  as  a  carrier  of  CO2  from  the  tissues  to  the  lungs,  and 
that  this  deficiency  could  only  be  made  up  by  a  greatly  increased 
circulation  rate,  if  it  was  made  up  at  all.  The  truth,  however,  is 
that  the  main  difference  produced  was  that  the  dead  weight  of 
CO2  always  carried  round  by  the  blood  was  greatly  diminished. 
As  a  carrier  of  CO2  from  the  tissues  to  the  lungs,  the  blood  was 

48  Amer.  Journ.  of  Physiol.,  LI,  p.  568,  1920. 


RESPIRATION 


197 


nearly  as  efficient  as  normal  blood.  This  is  due  to  the  fact  that,  as 
already  explained  in  Chapter  V,  the  haemoglobin  and  other  pro- 
teins play  the  essential  part  in  the  actual  conveyance  of  CO2  from 
the  tissues  to  the  lungs,  and  can  still  play  this  part  in  spite  of  what, 
in  a  physiological  sense,  is  extreme  acidosis. 

The  experiments  were  practically  a  replica  in  man  of  the  ex- 
periments of  Geppert  and  Zuntz  on  muscular  activity  in  dogs 
(Chapter  I).  In  discussing  these  experiments  Priestley  and  I  were 
not  aware  that  a  very  great  diminution  of  the  CO2  content  of  the 
blood  may  be  caused  by  acidosis  without  any  serious  diminution 
in  the  capacity  of  the  blood  for  conveying  CO2  from  the  tissues  to 
the  lungs.  The  discovery  made  in  1914  by  Christiansen,  Douglas, 
and  myself  has  greatly  altered  the  previously  existing  ideas  as  to 
the  conveyance  of  CO2  from  the  tissues. 

The  comparatively  rapid  recovery  of  the  blood  after  the  flood- 
ing of  the  body  with  lactic  acid  was  evidently  due  to  the  fact  that 
lactic  acid  was  rapidly  oxidized  before  the  slight  acidosis  actually 
produced  had  time  to  cause  any  considerable  extra  excretion  of 
acid  by  the  kidneys,  or  formation  of  ammonia  by  the  liver.  Had 
the  acidosis  been  produced  by  a  mineral  acid  it  would  probably 
have  taken  far  longer  to  pass  off. 

Disturbance  of  the  blood  reaction  may  be  artificially  produced 
by  the  ingestion  of  acids  or  alkalies,  or  even,  to  a  slight  extent,  by 
varying  the  character  of  the  diet.  It  requires  a  very  large  amount 
of  acid  or  alkali  to  produce  any  considerable  disturbance.  This  is 
partly  due  to  the  abundance  of  buffer  substances  in  the  body,  but 
still  more  to  the  effective  means  (variations  in  lung  ventilation, 
ammonia  formation,  and  excretion  of  acid  or  alkali  by  the  kid- 
neys) which  the  body  possesses  of  active  defence  against  dis- 
turbance of  reaction.  If  the  administration  of  acids  or  alkalies  is 
used  medicinally  as  a  means  of  assistance  in  the  regulation  of  the 
blood  reaction,  the  large  doses  required  must  be  borne  in  mind. 
Small  doses  cannot  but  be  practically  useless.  The  amelioration  of 
the  physiological  symptoms  of  acidosis  or  alkalosis  will  form  the 
safest  guide  to  what  is  required ;  but  it  is  evidently  very  important 
not  to  mistake  alkalosis  for  acidosis,  or  the  hyperpnoea  of  acidosis 
for  the  abnormal  breathing  caused  by  anoxaemia  or  an  exhausted 
or  "neurasthenic"  respiratory  center.  There  are  no  short  cuts  to 
decisions  on  such  a  subject.  A  physician  must  be  a  real  physician, 
and  must  have  learned  to  be  one  by  study  of  how  the  living  body 
behaves — of  what  its  <£iW  is,  to  use  the  old  expression  of  Hip- 
pocrates. 


1 98  RESPIRATION 

As  the  kidneys  are  essentially  concerned  in  the  regulation  of  the 
reaction  within  the  body,  it  is  evident  that  failure  of  the  kidneys 
may  cause  serious  disturbance  of  reaction.  As,  moreover,  normal 
human  urine  is  acid,  and  presumably  is  so  in  all  animals  if  food  is 
not  taken,  the  disturbance  will  naturally  be  in  the  direction  of 
producing  acidosis.  Hyperpnoea  and  other  symptoms  suggestive 
of  acidosis  are  commonly  met  with  as  an  accompaniment  of  serious 
inflammation  of  the  kidneys;  and  these  symptoms  are  now  com- 
monly attributed  to  acidosis.  One  peculiarity  of  them  is  that  there 
may  be  little  or  no  increase  in  the  ratio  of  ammonia  to  total  nitro- 
gen excreted. 

Considerable  new  light  is  thrown  on  the  causes  of  acidosis  by 
quite  recent  experiments  of  J.  B.  S.  Haldane.47  The  experiments 
consisted  in  taking  large  doses  of  NH4C1  during  two  or  three 
days,  so  that  an  abnormal  percentage  of  ammonia  was  present  in 
the  blood.  As  a  result  there  were  very  pronounced  respiratory 
and  other  symptoms  of  acidosis,  including  a  marked  fall  in  the 
available  alkali  of  the  blood.  Owing  to  the  excess  of  ammonia  in 
the  blood  part  of  the  ammonia  of  the  NH4C1  had  been  converted 
into  urea,  setting  free  much  HC1  into  the  blood.  The  normal 
response  in  which  the  liver  sets  free  ammonia  into  the  blood  on 
the  approach  of  acidosis  was  of  course  reversed,  and  though  the 
urine  was  very  acid  the  kidneys  were  unable  by  themselves  to 
cope  effectively  with  the  HC1,  so  that  acidosis  resulted. 

A  further  result  was  that  the  supply  of  phosphate  in  the  body 
began  to  run  short,  so  that  the  kidneys  could  not  excrete  so  much 
acid  as  usual  for  a  corresponding  acidosis.  When  neutralized 
sodium  phosphate  was  taken  the  excretion  of  acid  was  much 
increased,  and  the  acidosis  passed  off  correspondingly  more 
rapidly. 

These  experiments  are  of  special  interest,  as  they  revealed  a 
practicable  method  of  artificially  producing  marked  symptoms 
of  acidosis  in  man.  Previous  attempts  to  do  so  by  drinking  large 
quantities  of  dilute  HC1  or  acid  sodium  phosphate  had  failed 
owing  to  the  efficacy  of  the  physiological  means  of  regulation. 
It  seems  likely  that  in  the  acidosis  of  Bright's  disease  the  forma- 
tion of  ammonia  by  the  liver  is  checked  by  the  accumulation  of 
ammonia  in  the  blood  owing  to  the  inefficiency  of  the  kidneys. 
Hence  the  ratio  of  ammonia  to  total  nitrogen  in  the  urine  is  not 
increased. 

It  follows  from  the  facts  brought  forward  in  this  chapter  that 

4T  J.  B.  S.  Haldane,  Journ.  of  Physiol.,  LV,  1921. 


RESPIRATION  199 

the  regulation  of  alveolar  and  arterial  CO2  pressure  resolves  itself 
into  regulation  of  the  blood  reaction,  and  that  the  blood  reaction 
itself  is  a  normal  which  is  constantly  being  regulated  within 
marvelously  narrow  limits — so  narrow  that  the  variations,  evident 
though  they  are  made  by  physiological  reactions,  cannot  be  fol- 
lowed adequately  by  existing  physical  and  chemical  methods. 

At  this  point  it  seems  desirable  to  consider  and  criticize  some  of 
the  indirect  means  which  have  been  used  for  estimating  variations 
in  the  hydrogen  ion  concentration  of  the  blood.  In  recent  years  the 
capacity  of  the  blood,  or  of  its  serum,  for  combining  with  CO2  has 
commonly  been  taken  as  an  index  of  hydrogen  ion  concentration, 
this  capacity  being  also  alluded  to  as  a  measure  of  the  "alkaline  re- 
serve" of  the  blood.  It  is  evident  that  the  "alkaline  reserve"  of  the 
blood  is  only  another  name  for  the  "titration  alkalinity"  when  CO2 
is  allowed  to  escape.  It  is  also  evident  from  facts  described  above 
that  the  alkaline  reserve  is  increased  in  conditions  of  acute  acidosis 
due  to  excess  of  CO2,  and  diminished  in  conditions  of  acute  al- 
kalosis  due  to  excessive  lung  ventilation  caused  by  artificial  res- 
piration or  anoxaemia.  Hence  although  the  alkaline  reserve  is 
diminished  in  acidosis  due  to  the  presence  of  abnormal  acids  in 
the  blood,  a  diminution  in  alkaline  reserve  cannot  be  regarded  as 
by  itself  an  index  of  acidosis.  There  is,  in  fact,  no  necessary  con- 
nection between  diminution  in  alkaline  reserve  or  titration  alka- 
linity and  diminution  in  blood  alkalinity. 

Another  indirect  method  which  has  been  used  for  estimating 
variations  in  alkalinity  is  observation  of  one  or  more  points  in  the 
dissociation  curve  of  the  oxyhaemoglobin  of  the  blood  in  presence 
of  the  existing  alveolar  CO2  pressure.  This  method  is  due  to 
Barcroft  and  his  pupils,  and  is  based  on  the  following  facts.  ( I ) 
As  was  shown  in  Chapter  IV,  each  point  in  the  dissociation  curve 
of  oxy-  or  CO-haemoglobin  in  blood  is  simply  displaced  to  a  pro- 
portional distance  to  the  right  or  left  on  varying  within  wide  limits 
the  partial  pressure  of  CO2.  Thus  only  one  constant  in  the  equa- 
tion expressing  the  curve  is  altered.  (2)  It  was  shown  by  Peters,48 
and  this  had  been  completely  confirmed  by  Hasselbalch,49  that  the 
alteration  in  the  constant  depends,  in  cases  where  only  the  CO2 
pressure  is  varied,  on  alterations  in  the  hydrogen  ion  concentra- 
tion, and  can  thus  be  used  as  a  measure  of  it.  Barcroft  and  others 
have  therefore  used  the  alteration  in  the  constant  as  a  measure  in 
all  cases  of  variation  of  hydrogen  ion  concentration  in  the  blood. 

48  Barcroft,  The  Respiratory  Functions  of  the  Blood,  p.  316. 

49  Hasselbalch,  Biochem.  Zeitschr.,  78,  p.  132,  1916. 


200  RESPIRATION 

In  persons  at  high  altitudes,  for  instance,  the  constant  is  appar- 
ently quite  normal  in  presence  of  the  existing  alveolar  CO2  pres- 
sure; and  from  this  fact  it  was  inferred  that  the  hydrogen  ion 
concentration  of  the  blood  is  also  normal,  as  already  mentioned. 
On  the  other  hand,  in  persons  who  have  shortly  before  undergone 
some  excessive  muscular  exertion  the  constant  is  very  markedly 
altered ;  and  from  this  fact  a  corresponding  increase  of  hydrogen 
ion  concentration  in  the  blood  is  inferred.  The  same  method  has 
been  employed  for  estimating  variations  of  hydrogen  ion  con- 
centration in  the  blood  of  patients. 

When,  however,  the  facts  are  examined  more  closely  it  appears 
that  there  must  be  a  flaw  in  the  reasoning.  In  the  case  of  persons 
who  have  completed  some  severe  muscular  exertion  in  a  few  min- 
utes before,  there  is  no  physiological  evidence  of  anything  but  a 
most  trifling  acidosis,  such  as  could  not  possibly  be  detected  by 
alterations  in  the  constant  of  the  dissociation  curve.  The  breathing 
is  only  increased  to  such  an  extent  as  to  reduce  the  alveolar  CO2 
pressure  by  about  a  fifth.  This  only  corresponds  to  an  acidosis 
equivalent  to  what  would  be  produced  by  a  rise  of  0.3  mm.  in  the 
alveolar  CO2  pressure ;  and  such  a  rise  would  be  entirely  inappreci- 
able in  its  effect  on  the  dissociation  curve  of  oxyhaemoglobin.  The 
rise  apparently  indicated  by  the  alteration  in  the  constant  is  enor- 
mously greater.  Hence  it  appears  that  there  must  be  some  other 
cause  for  the  alteration  than  rise  in  hydrogen  ion  concentration. 
This  other  cause  is  probably  operative  in  many  cases  of  patho- 
logical acidosis. 

Another  indirect  method  of  measuring  hydrogen  ion  concen- 
tration has  been  proposed  by  Hasselbalch.50  He  showed  quite 
clearly  that  when  the  pressure  of  CO2  is  varied  in  blood  or  even 
serum  the  hydrogen  ion  concentration,  as  separately  determined, 
is  proportional  to  the  ratio  of  combined  CO2  (which,  as  already 
explained,  is  a  measure  of  the  bicarbonate  present)  to  free  CO2 
when  allowance  is  made  for  the  percentage  ionization  of  the  free 
CO2  and  bicarbonate.  This  corresponds  with  the  fact  that  the  blood 
behaves  as  if  more  alkali  were  constantly  being  added  to  it  in  pro- 
portion as  its  reaction  approaches  the  neutral  point.  It  is  very  re- 
markable how  closely  Hasselbalch's  law  holds  for  different  kinds 
of  blood  and  in  blood  serum,  in  spite  of  great  differences  in  the 
dissociation  curves  for  CO2.  Figure  58  from  Hasselbalch's  paper 
is  also  very  interesting  as  showing  (for  fresh  ox  blood)  the  dif- 
ferences in  the  dissociation  curves  for  serum,  blood,  and  corpuscles. 

60  Hasselbalch,  Biochem.  Zeitsckr.,  78,  p.  112,  1916. 


RESPIRATION 


201 


These  differences  are  just  what  might  be  expected  in  view  of  the 
action  of  haemoglobin  as  a  weak  acid  in  alkaline  solutions.  In  spite 
of  the  great  differences  in  the  dissociation  curves  of  blood  and 
serum  Hasselbalch's  law  held  good.  He  therefore  applied  it  as  a 
means  of  calculating  the  hydrogen  ion  concentration  of  corpuscles 
and  of  abnormal  blood,  and  seemed  justified  in  doing  so. 


Vol  % 


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10     tO     30     40     50    60     70     SO     SO 

• .  Serum,  38° 

Blood,  1 8° 
Blood,  38° 
Blood  corpuscles,  38° 
Serum,  18° 

Figure  58. 
COa  dissociation  curves  (from  Hasselbalch  loc.  cit.) 

Nevertheless  this  method,  like  that  of  Barcroft  and  Peters, 
seems  to  break  down  with  abnormal  blood.  As  an  example  of 
abnormal  blood  he  took,  from  the  paper  already  referred  to  by 
Christiansen,  Douglas,  and  myself,  experiments  in  which  Douglas 
had  flooded  his  blood  with  lactic  acid  by  running  quickly  a  number 
of  times  up  and  down  the  laboratory  stairs  at  intervals  during 
about  a  quarter  of  an  hour.  As  a  consequence  his  blood  had  lost 
about  40  per  cent  of  its  normal  power  of  combining  with  CO2,  and 
his  resting  alveolar  CO2  pressure  was  diminished  by  about  a  fifth. 
The  samples  were  taken  about  ten  minutes  after  the  last  ascent  of 
the  stairs,  and  all  sensible  hyperpnoea  had  passed  off.  From  the 
data  given,  Hasselbalch  calculates,  in  accordance  with  the  law 
he  had  discovered  for  the  same  blood  at  varying  pressures  of  CO2, 
that  the  PH  of  Douglas's  arterial  blood  had  fallen  by  .12.  This 
would,  in  accordance  with  the  data  given  above  as  to  the  effects 
of  increase  of  PH  on  the  breathing,  suffice  to  increase  the  breath- 
ing to  about  ten  times  its  resting  value.  Indeed  Hasselbalch  evi- 
dently believed  that  there  must  have  been  such  an  increase,  since 
he  speaks  of  the  immensely  increased  breathing  being  unable  to 
compensate  for  the  decrease  in  PH.  The  breathing  was,  however, 
perfectly  quiet  and  apparently  normal,  though  the  lowering  of 


202  RESPIRATION 

the  alveolar  CO2  pressure  showed  that  it  was  about  a  fourth  deeper 
than  it  otherwise  would  have  been.  On  the  physiological  evidence, 
therefore,  the  fall  in  PH  was  only  about  .003,  instead  of  .12,  or 
only  one-fortieth  as  much  as  calculated.  From  this  example  it 
would  seem  to  follow  that  Hasselbalch's  method,  when  extended 
to  abnormal  blood,  is  as  unreliable  as  that  of  Barcroft  and  Peters. 
Further  investigation  as  to  methods  of  determining  hydrogen  ion 
concentration  in  abnormal  blood  seems  to  be  much  needed. 

Except  by  observation  of  physiological  reactions,  there  seems  at 
present  to  be  no  method  of  estimating  in  a  reliable  manner  the 
small  variations  in  PH  which  are  of  so  much  physiological  impor- 
tance. Hasselbalch  estimates  that  a  difference  of  .03  can  be  detected 
in  single  determinations  by  the  electrometrical  method ;  but  this  is 
a  very  large  difference,  corresponding  to  an  increase  of  250  per 
cent  in  the  breathing.  The  colorimetric  method  by  means  of  indi- 
cators is  equally  rough.  Time  and  effort  will  continue  to  be  wasted 
on  futile  measurements  until  the  extreme  fineness  of  the  physio- 
logical regulation  of  PH  in  the  blood  and  tissues  is  more  fully 
realized. 


REACTION  OF  THE  BLOOD  IN  EIGHT  DIFFERENT  WOMEN 

BEFORE  AND 

AFTER 

CHILDBIRTH 

PH.  at 
40  mm. 
Before 

CO2  pressure 
After 

Alveolar  CO2 
pressure 
Before        After 

PH  at  alveolar 
COi  pressure 
Before        After 

7.40 
7.40 
7-45 

7-44 
7.48 
7-45 

31.0 
27.7 

35-6 

42.2 

43-5 
39«8 

7-44           7-43 
7.49           7.46 

7.48         7-45 

7-39 

7-43 

32.5 

43-5 

7.42           7.42 

7-39 
7-38 
7.38 

7-35 

7-44 
7-45 
7-43 
7.38 

32.7 
27-7 
30.3 
33-8 

37-7 
33-5 
38.3 
37-3 

7-43           7-45 
7-45           7-49 
7.4i         7-44 
7.38         7.40 

Mean      7.39 

7-44 

3i.3 

39-5 

7-44         7-44 

On  account  of  various  sources  of  error,  already  alluded  to,  in 
the  electrometrical  or  other  measurements  of  PH,  we  are  still  with- 
out much  very  exact  information  as  to  the  permanent  steadiness 
during  health  of  the  alkalinity  of  the  blood  under  resting  condi- 
tions. In  this  connection  some  very  interesting  observations  have 
been  made  by  Hasselbalch  and  Gammeltoft  on  the  PH  of  the 


RESPIRATION  203 

blood  during  and  after  pregnancy.51  It  had  already  been  found 
by  Hasselbalch  and  others  that  the  alveolar  CO2  pressure  is  much 
lower  than  normal  during  pregnancy.  Taking  advantage  of  this 
fact,  they  determined  the  PH  of  arterial  blood  before  and  after 
childbirth  with  the  results  shown  in  the  accompanying  table. 

Allowing  for  the  probable  errors  in  determining  the  PH  and 
alveolar  CO2  pressure,  these  figures  seem  to  show  that  the  fall  in 
alveolar  CO2  pressure  compensates  within  the  limits  of  accuracy  of 
the  electrometric  method  for  the  fall  in  the  PH  of  the  blood  which 
would  otherwise  occur.  The  mean  of  the  first  two  columns  shows 
that  this  fall  in  PH  would  have  been  0.05,  whereas  the  compen- 
sating fall  in  alveolar  CO2  pressure  was  8.2  mm.  as  shown  by  the 
mean  for  the  second  two  columns.  Hence  a  difference  of  o.oi  in 
PH  corresponds  to  a  difference  of  1.6  mm.  of  CO2  pressure,  or 
0.23  per  cent  of  CO2  in  alveolar  air.  We  have  already  seen,  how- 
ever, that  a  change  of  about  this  amount  in  alveolar  CO2  pressure 
is  sufficient  to  cause  either  apnoea  or  doubling  of  the  alveolar 
ventilation  according  to  its  direction.  Even  under  the  most  favor- 
able conditions  it  is  hardly  possible  at  present  to  determine  differ- 
ences in  PH  within  the  body  to  within  0.03  in  single  observations; 
but  by  measuring  the  variations  in  lung  ventilation  as  compared 
with  production  of  CO2  we  have  an  index  of  change  in  PH  which 
is  at  least  50  times  as  sensitive  as  the  existing  direct  electrometric 
method,  exact  as  this  is  in  comparison  with  older  methods. 

Although  the  measurements  of  PH  showed  no  change  in  the 
alkalinity  of  the  blood  during  pregnancy,  yet  the  fall  in  alveolar 
CO2  pressure  indicated  that  there  was  an  increase  of  25  per  cent  in 
the  lung  ventilation  per  unit  of  CO2  given  off.  This,  therefore, 
would  correspond  to  an  "acidosis"  to  the  extent  of  a  PH  of  0.003 — 
an  amount  far  too  small  for  direct  measurement.  That  it  was 
acidosis  which  caused  the  increase  in  the  breathing  was  shown  by 
the  fact  that  the  increase  was  accompanied  by  an  increase  of  about 
20  per  cent  in  the  proportion  of  nitrogen  excreted  as  NH3  to  total 
nitrogen  excreted  in  the  urine.  The  authors  conclude  that  there  is 
an  increased  acid  production  in  the  body  during  pregnancy  (or 
perhaps  an  increased  drain  of  alkali  from  the  body  of  the  mother) , 
but  that  it  is  compensated  by  increased  breathing  and  formation 
of  NH3.  It  is  true  that  relatively  to  the  degree  of  accuracy  at 
present  attainable  in  determining  the  PH  of  blood  the  compensa- 
tion is  perfect.  But  if  the  compensation  were  really  perfect  we 
should  be  landed  in  the  position  of  the  vitalists  of  assuming  effects 

"Hasselbalch  and  Gammeltoft,  Biochem.  Zeitschr.,  68,  p.  206,  1915. 


204  RESPIRATION 

produced  without  any  measureable  cause.  In  reality  the  acidosis 
is  not  completely  compensated,  and  the  incompleteness  is  only 
hidden  by  the  extreme  roughness  of  the  method  of  measurement 
in  comparison  with  the  fineness  of  the  physiological  reaction. 

The  table  seems  to  indicate  that  the  normal  PH  is  not  quite  the 
same,  though  very  nearly  the  same,  in  different  individuals.  For 
the  present,  however,  this  conclusion  is  rather  doubtful,  in  view 
of  the  fact  that  the  measurements  were  for  imperfectly  reduced 
blood.  We  have  seen  already  that  in  spite  of  the  accuracy  of  regu- 
lation there  are  individual  differences  in  the  normal  alveolar  CO2 
pressure,  the  normal  composition  of  haemoglobin,  and  the  normal 
dissociation  curve  of  blood  for  CO2.  As  regards  every  detail  of 
structure  and  function  we  may  be  certain  of  rinding  similar  differ- 
ences when  the  measurements  are  made  with  sufficient  accuracy; 
and  this  doubtless  applies  also  to  even  the  PH  of  the  blood. 

We  have  already  considered  one  cause  which  alters  the  PH  to 
which  the  respiratory  center  regulates.  This  cause  is  anoxaemia. 
At  high  altitudes  the  body  is  in  the  long  run  projected  to  a  large 
extent  from  the  effects  of  the  alkalosis  thus  produced,  because  the 
kidneys  and  liver  still  react  almost  true  to  the  normal  PH.  There 
can  be  no  doubt  that  other  causes,  such  as  the  action  of  anaes- 
thetics or  poisons,  or  of  other  small  changes  in  the  composition  of 
the  blood,  would  have  a  similar  effect  in  altering  the  standard 
to  which  the  PH  regulation  of  the  arterial  blood  is  set.  This 
question,  and  the  question  how  the  PH  is  regulated,  not  merely  in 
the  arterial  blood,  but  in  the  systemic  capillaries,  will  be  deferred 
to  Chapters  X  and  XIV. 

We  can  now  see  much  more  clearly  why  it  is  that  the  resting 
alveolar  CO2  pressure  is  not  quite  steady  in  spite  of  the  extreme 
sensitiveness  of  the  respiratory  center  to  the  minutest  variation 
in  alveolar  CO2  pressure.  There  are  various  causes  tending  to 
disturb  the  constancy  of  the  reaction  of  the  blood ;  and  the  respira- 
tory center,  and  not  merely  the  kidneys  and  liver,  must  do  its  share 
in  compensating  for  these  disturbances.  Hence  the  alveolar  CO2 
pressure  cannot  remain  completely  steady  during  rest.  One  of 
these  causes  is  the  secretion  of  acid  or  alkaline  digestive  juices. 
On  account  of  the  secretion  of  acid  gastric  juices  the  alveolar 
CO2  pressure  rises  distinctly  very  soon  after  a  meal.  The  effects  of 
a  meal  on  alveolar  CO2  pressure  have  been  investigated  recently 
by  Dodds.52  He  found  that  there  is  normally  a  sharp  rise  varying 
in  different  individuals,  but  usually  amounting  to  about  4  mm.  half 

82  Dodds,  Journ.  of  Physiol.,  LIV,  p.  342,  1921. 


RESPIRATION  205 

an  hour  after  the  meal.  This  is  rapidly  followed  by  an  equally 
marked  fall  below  normal,  culminating  about  one  and  one-half 
hours  after  the  meal,  with  a  subsequent  rapid  return  to  normal. 

Bennett  and  Dodds53  have  found  that  the  rise  of  alveolar  CO2 
just  after  a  meal  is  closely  related  to  the  concentration  and  rate 
of  secretion  of  the  gastric  hydrochloric  acid  as  indicated  by 
samples  taken  from  the  stomach.  In  cases  where  there  is  little  or 
no  secretion  of  HC1  the  rise  in  alveolar  CO2  is  absent,  though  the 
fall  due  to  alkaline  secretion  into  the  intestine  is  still  present. 
Another  cause  of  variation  in  alveolar  CO2  pressure  is  the  charac- 
ter of  the  diet.  With  an  alkali-forming  vegetable  diet  the  alveolar 
CO2  pressure  is  quite  considerably  higher  than  with  an  acid-form- 
ing meat  diet.  This  was  brought  out  very  clearly  in  some  of  the 
experiments  of  Hasselbalch  alluded  to  above;  and  he  showed  at 
the  same  time  that  the  reaction  of  the  urine  varied  in  correspond- 
ence with  the  changes  in  alveolar  CO2  pressure. 

During  starvation  the  body  is  living  on  what  amounts  to  an 
acid-forming  diet,  and  Higgins54  has  shown  that  during  starva- 
tion the  alveolar  CO2  pressure  falls.  Perhaps  the  most  striking 
effects  are  obtained  with  a  carbohydrate-free  diet.  This  leads  to 
the  formation  within  the  body  of  a  certain  amount  of  aceto-acetic 
and  oxybutyric  acids,  as  in  severe  diabetes.  Higgins,  Peabody, 
and  Fitz55  showed  that  there  is  a  striking  fall  in  alveolar  CO2 
pressure,  together  with  a  very  large  elimination  of  oxybutyric  and 
aceto-acetic  acid  by  the  kidneys,  and  an  accompanying  large  in- 
crease in  ammonia  excretion  and  excretion  of  acid. 

All  the  available  evidence  points,  therefore,  to  the  conclusion 
that  practically  speaking  the  regulation  of  breathing  in  man  dur- 
ing rest  under  normal  conditions  is  regulation  of  the  blood  re- 
action. This  very  important  conclusion  is  the  outcome  of  the 
present  chapter. 

Addendum.  Within  the  limits  of  the  present  book  it  is  un- 
fortunately impossible  to  deal  in  detail  with  the  mass  of  quite 
recent  literature  bearing  on  the  regulation  of  blood  alkalinity. 
Some  of  this  literature  is  based  on  assumptions  with  which,  for 
the  reasons  already  given,  I  am  unable  to  agree :  while  other  parts 
of  it  are  concerned  with  details  as  to  which  it  seems  difficult  for 
the  present  to  form  definite  judgments.  In  general,  however,  it 

K  Bennett  and  Dodds,  Brit.  Journ.  of  Exper.  Pathol.,  II,  p.  58,  1921. 
"Higgins,   Publication  No.   203,   Carnegie  Institution  of   Washington,  p.    168, 

- 

Higgins,  Peabody,  and  Fitz,  Journ.  of  Med.  Research,  XXXIV,  p.  263,  1916. 


206  RESPIRATION 

does  not  appear  to  me  that  anything  which  has  recently  been 
published,  points  to  any  important  modification  of  the  conclu- 
sions embodied  in  this  chapter.  In  view  of  the  great  confusion 
which  evidently  exists  as  to  the  subject,  it  may,  nevertheless,  be 
useful  to  indicate  more  explicitly  the  reasons  for  regarding  the 
words  "acidosis"  and  "alkalosis"  as  denoting  deviations  towards 
the  acid  or  alkaline  side  respectively  of  the  normal  reaction  or 
hydrogen-ion  concentration  within  the  body. 

Acidosis  and  alkalosis  are  now  frequently  regarded  as  condi- 
tions in  which,  whether  or  not  there  is  an  alteration  in  actual 
reaction,  the  "alkaline  reserve"  of  the  blood  plasma  is  diminished 
or  increased.  This  definition  originated  in  a  paper  by  Van  Slyke 
and  Cullen  in  which  they  pointed  out  the  ease  with  which  varia- 
tions in  the  "alkaline  reserve,"  or  total  capacity  of  the  blood 
plasma  for  combining  with  CO2  can  be  determined  experimentally, 
and  the  advantages  of  using  oxalated  blood  plasma  in  place  of 
whole  blood  for  the  purpose.56  Though  they  stated  clearly  that 
variations  in  alkaline  reserve  are  no  direct  measure  of  the  varia- 
tions in  actual  reaction  of  the  blood,  they,  very  unfortunately  as 
I  think,  proceeded  to  define  "acidosis"  as  simply  a  condition  in 
which  the  alkaline  reserve  of  the  blood  is  diminished.  It  is,  how- 
ever, to  variations  in  reaction,  and  not  in  the  conveniently  meas- 
ured alkaline  reserve  of  the  plasma  that  the  body  is  reacting 
in  conditions  of  acidosis  or  alkalosis;  and  to  define  acidosis  or 
alkalosis  as  anything  else  than  a  deviation  towards  the  acid  or 
alkaline  side  of  the  normal  reaction  seems  to  me  quite  unjustifiable. 

The  confusion  has  been  added  to  by  the  general  failure  to 
realize  the  extreme  delicacy  of  physiological  regulation  of  re- 
action, as  compared  with  the  comparative  roughness  of  our  present 
means  of  directly  measuring  changes  in  reaction.  Thus  in  cases 
where  there  are  all  the  physiological  signs  of  acidosis,  the  avail- 
able means  of  direct  measurement  may  show  no  sign  of  the 
change;  and  hence  it  has  been  quite  wrongly  assumed  that  no 
change  exists.  This  has  contributed  towards  an  acceptance  of  the 
definition  of  acidosis  as  a  condition,  not  of  increased  hydrogen- 
ion  concentration. within  the  body,  but  of  diminished  alkaline  re- 
serve. The  picturesque  expression  "alkaline  reserve"  is  evidently 
an  unfortunate  one  in  so  far  as  it  suggests  a  reserve  of  alkali  not 
in  actual  use.  The  alkali  weakly  combined  in  the  body  is  in  reality 
always  in  physiological  use,  and  the  most  urgent  symptoms  of 
acidosis  appear  long  before  the  alkaline  reserve  disappears. 

"Van  Slyke  and  Cullen,  Journ.  of  Biol.  Chem.,  XXX,  p.  289,  1917. 


RESPIRATION 


207 


As  was  shown  above,  a  difference  of  .012  in  the  PH  of  the  blood 
is  sufficient  to  double  the  resting  breathing,  or  cause  apnoea.  This 
difference  in  PH  corresponds  to  a  difference  of  only  about  one 
part  by  weight  of  ionized  hydrogen  in  a  million  million  parts  of 
blood.  A  continued  difference  of  o.  I  in  PH  would  in  all  probability 
cause  danger  to  life.  This  is  a  much  lower  limit  than  has  commonly 
been  assumed.  By  forced  breathing  we  can,  it  is  true,  produce  a 
greater  difference  in  the  PH  of  arterial  blood,  and  maintain  this 
difference  for  an  hour  or  more  without  loss  of  consciousness.  The 
difference,  however,  applies  only  to  the  arterial  blood.  As  will  be 
shown  in  Chapter  X,  slowing  of  the  circulation  protects  the  tissues 
to  a  large  extent  from  great  rises  in  PH.  It  is  possible,  also,  that  ac- 
tive secretion  of  CO2  by  the  lungs,  as  well  as  quickening  of  the  cir- 
culation, protects  similarly  against  fall  in  the  PH  of  the  tissues. 
Nevertheless,  as  Yandell  Henderson  has  so  clearly  shown,  when 
efficient  forced  respiration  is  kept  up  in  animals  for  a  sufficient 
time,  not  only  do  coma  and  progressive  failure  of  circulation  ensue, 
but  so  much  damage  is  done  that  it  is  impossible  to  recover  the  ani- 
mal on  restoring  the  PH  of  the  blood  by  administering  CO2,  just  as 
it  is  impossible  to  recover  a  patient  who  has  suffered  for  a  sufficient 
time  from  acute  anoxaemia.  That  progressive  and  often  irrepar- 
able damage  ensues  also  during  a  condition  of  excessive  acidosis 
is  suggested  by  the  phenomena  of  CO2  poisoning  and  clinical 
acidosis.  To  what  extent  the  damage  during  alkalosis  is  due  di- 
rectly to  the  rise  in  PH,  or  to  the  accompanying  anoxaemia,  we 
cannot  at  present  say;  and  perhaps  the  question  is  at  bottom 
merely  academic.  When  the  forced  breathing  is  of  oxygen  instead 
of  air  the  effects  are  much  less  marked,  as  mentioned  above;  but 
this  may  be  because  the  circulation  can  be  shut  down  more  effec- 
tively when  oxygen  is  breathed,  and  that  hence  the  rise  in  PH  in 
the  tissues  is  diminished. 


CHAPTER  IX 
Gas  Secretion  in  the  Lungs. 

IN  the  lungs  the  blood  is  separated  from  the  alveolar  air  by  two 
layers  of  living  tissue,  namely  the  capillary  endothelium  and  the 
alveolar  epithelium.  What  part  in  respiratory  exchange  is  played 
by  these  very  thin  layers  of  living  tissue?  Is  this  part  purely  me- 
chanical? In  other  words,  do  these  layers  behave  towards  the 
respiratory  gases  as  any  very  thin  non-living  moist  membrane 
would  behave?  Or  do  the  living  membranes  play  an  active  part  in 
the  process?  We  must  now  face  this  interesting,  but  also  contro- 
versial subject. 

There  has  been  a  tendency  to  assume  that  because  these  mem- 
branes are  very  thin  they  cannot  play  any  active  part.  But  it  is  not 
so  long  since  even  membranes  consisting  of  cubical  or  columnar 
epithelial  cells  were  supposed  only  to  play  a  passive  part  in  the 
separation  of  material;  and  the  presumption  that  a  thinner  mem- 
brane of  flattened  cells  cannot  play  an  active  part  has  come  down  to 
us  from  the  time,  about  the  middle  of  last  century,  when  physico- 
chemical  theories  became  dominant  in  physiology,  and  secretion  in 
general  was  supposed  to  be  a  mere  mechanical  process  like  filtra- 
tion or  diffusion.  Another  prevalent  presumption  is  that  though 
liquids  or  dissolved  solids  may  be  actively  secreted,  gases  probably 
pass  through  living  membranes  by  simple  diffusion. 

So  little  information  about  gas  secretion  is  usually  to  be  found 
in  physiological  text  books  that  it  may  be  useful,  before  discussing 
gas  secretion  by  the  lungs,  to  give  some  account  of  gas  secretion 
as  it  is  now  well  known  to  exist  in  the  swim  bladder  of  fishes. 

The  swim  bladder  is  morphologically  a  diverticulum  of  the 
alimentary  canal,  like  the  lungs.  In  some  classes  of  fishes  there  is 
an  open  duct  from  the  swim  bladder  into  the  alimentary  canal, 
but  in  other  classes  this  duct  is  closed.  Quite  evidently,  the  main 
function  of  the  swim  bladder  is  to  make  the  specific  gravity  of  the 
fish  about  equal  to  that  of  the  water  it  displaces  when  the  fish  is 
at  a  certain  depth.  With  a  certain  amount  of  gas  in  its  swim 
bladder  the  fish  will  just  float  at  a  certain  depth.  It  is,  however, 
in  a  position  of  unstable  equilibrium :  for  any  movement  upwards 
will  cause  expansion  of  the  air,  so  that  the  fish  will  tend  to  rise 
with  increasing  velocity  towards  the  surface ;  and  any  movement 


RESPIRATION  209 

downwards  from  the  position  of  equilibrium  will  similarly  tend 
to  make  the  animal  sink  with  increasing  velocity  to  the  bottom. 
When  fishes  are  stunned  by  an  explosion  under  water,  about  half 
of  them  float  to  the  top,  and  the  other  half  sink  to  the  bottom. 
One  has  only  to  place  a  goldfish  in  a  large  and  tall  bottle  of 
water  provided  with  a  perforated  cork  through  which  a  thick 
walled  tube  containing  water  passes  to  another  small  bottle  of 
water,  in  order  to  see  how  the  fish  deals  with  the  situation.  If  the 
pressure  in  the  large  bottle  is  raised  by  raising  the  small  bottle 
the  fish  will  at  first  begin  to  sink,  but  will  immediately  turn  its 
nose  upwards  and  swim  upwards,  so  as  to  reestablish  its  position 
of  unstable  equilibrium;  and  conversely  if  the  large  bottle  be 
lowered.  It  was  formerly  believed  that  a  fish  compresses  or  relaxes 
its  swim  bladder  when  it  wishes  to  go  downwards  or  upwards. 
That  this  is  not  the  case  was  shown  by  Moreau1  in  a  series  of 
beautiful  experiments.  A  fish  is  really  confined  temporarily  to 
about  a  certain  depth  by  its  swim  bladder ;  for  if  any  cause  tends 
to  make  it  leave  this  depth  the  animal's  response  to  the  stimulus 
of  expansion  or  contraction  of  its  swim  bladder  soon  brings  it 
back  to  its  proper  depth. 

The  goldfish  has  an  open  duct  to  its  swim  bladder,  so  if  the 
pressure  is  greatly  diminished,  as  by  connecting  the  large  bottle 
to  a  filter  pump,  the  air  of  the  swim  bladder  comes  bubbling  out 
of  the  animal's  mouth.  If  the  pressure  is  now  restored  to  normal 
the  animal  sinks  to  the  bottom,  and  after  a  few  fruitless  efforts 
to  swim  upwards  lies  helpless  on  its  side.  If  it  is  left  there  for  some 
time,  however,  it  gradually  becomes  more  buoyant,  and  after  a 
certain  number  of  hours  it  will  be  swimming  about  as  usual,  with 
its  swim  bladder  full  of  gas.  If  a  fish  has  a  closed  swim  bladder, 
and  the  gas  from  this  is  removed  by  means  of  a  hypodermic 
syringe,  the  fish  also  sinks  at  first,  but  soon  refills  its  swim  bladder 
with  gas.  How  is  this  gas  produced,  and  what  is  it?  It  cannot  have 
been  swallowed  as  air,  as  the  fish  has  been  lying  in  water  at  the 
bottom  all  the  time,  or  has  a  closed  swim  bladder.  This  brings 
us  to  gas  secretion. 

About  the  beginning  of  last  century  the  eminent  French  physi- 
cist Biot  was  engaged  in  survey  work  in  the  Mediterranean,  and 
was  attracted  by  the  observation  that  fishes  caught  with  a  line  at 
great  depths  come  to  the  surface  and  lie  helpless  with  their  swim 
bladders  distended  with  gas  and  sometimes  projecting  out  through 
the  mouth.  He  determined  to  analyze  the  gas,  and  having  intro- 

1  Moreau,  Memoires  de  PAysiologie,  Paris,  1877. 


210  RESPIRATION 

duced  some  of  it,  along  with  excess  of  hydrogen,  into  a  glass 
"eudiometer"  he  passed  a  spark.  Instead  of  the  mild  explosion 
usual  in  air  analyses,  there  was  a  violent  explosion  which  broke 
his  instrument.  He  then  knew  that  he  had  made  a  most  significant 
discovery,  as  the  gas  he  was  analyzing  must  be  nearly  pure  oxy- 
gen. He  got  another  eudiometer  and  made  a  number  of  analyses  of 
gas  from  the  swim  bladder.  The  results  showed  that  while  the 
gas  taken  from  the  swim  bladder  of  a  fish  near  the  surface  often 
contained  less  oxygen  than  ordinary  air,  that  taken  from  fishes 
caught  at  great  depths  contained  nearly  pure  oxygen.2  Biot  had 
discovered  oxygen  secretion. 

To  illustrate  the  real  significance  of  his  observations  we  may 
take  an  analysis  made  much  more  recently  by  Schloesing  and 
Richard,3  in  connection  with  which  the  depth  from  which  the 
fish  was  taken  is  definitely  stated,  and  was  4,500  feet.  They  found 
that  the  gas  contained  84.6  per  cent  of  oxygen,  together  with  3.6 
per  cent  of  CO2  and  n.8  per  cent  of  nitrogen.  The  latter  gases 
are,  however,  quite  likely  to  have  mostly  got  in  by  diffusion  during 
the  delay  before  the  sample  was  taken.  Now  the  pressure  at  4,500 
feet  is  136  atmospheres.  Therefore  the  oxygen  pressure  in  the 

Q  i    fZ 

swim  bladder  was  at  least  I36x  —  —  =  115  atmospheres,  while 

i  oo 

the  oxygen  pressure  in  the  sea  water  was  only  about  21  per  cent 
of  an  atmosphere,  and,  in  the  blood  circulating  in  the  capillaries 
round  the  swim  bladder,  certainly  very  much  less.  At  a  moderate 
estimate  the  oxygen  pressure  on  the  inside  of  the  wall  of  the 
swim  bladder  was  at  least  1,000  times  greater  than  in  the  cap- 
illaries outside. 

In  the  monograph  already  referred  to,  Moreau  described  a 
number  of  experiments  showing  the  conditions  under  which  oxy- 
gen secretion  into  the  swim  bladder  occurs.  He  found,  for  instance, 
that  if  a  fish  confined  in  an  open  cage  was  sunk  to  a  considerable 
depth,  so  that  its  specific  gravity  became  greater  than  that  of  the 
water,  it  gradually  secreted  oxygen  so  as  to  restore  the  balance ; 
and  similarly  if  its  swim  bladder  had  been  emptied  by  puncturing. 
The  simple  experiment  on  the  goldfish  which  I  have  just  described 
is  of  the  same  nature.  Moreau  even  found  that  if  a  weight  was 
attached  to  one  fish  in  an  experimental  tank,  and  a  float  to  another 
fish,  so  that  the  first  fish  was  for  the  time  glued  to  the  bottom,  and 
the  second  to  the  surface,  both  fishes  would  soon  be  swimming 

a  Biot,  Memoir es  de  la  Societe  d'Arcueil,  1807. 
3  Comptes  rendus,  Vol.  122,  p.  615,  1896. 


RESPIRATION  21 1 

about  again  quite  unconcerned  in  the  tank,  their  respective  swim 
bladders  having,  compensated  by  secretion  or  absorption  of  gas 
for  the  disturbance  in  equilibrium  caused  by  the  sinker  or  float. 

Such  facts  as  these  pointed  to  the  conclusion  that  the  gas  secre- 
tion is  under  the  control  of  the  nervous  system ;  but  this  was  not 
clearly  demonstrated  by  Moreau.  It  was  not  till  sixteen  years 
later  that  Bohr  showed  that  the  secretion  after  emptying  the 
swim  bladder  by  puncture  ceases  after  the  branch  of  the  vagus 
supplying  the  swim  bladder  is  cut.4  I  well  remember  the  interest 
with  which  I  saw  this  experiment  when  Bohr  showed  it  while  he 
was  staying  with  me  in  Oxford  a  few  months  before  he  published 
his  paper  on  the  subject.  Dreser5  had  meanwhile  already  shown 
that  the  secretion  of  oxygen,  like  that  of  saliva,  sweat,  etc.,  is 
excited  by  the  action  of  pilocarpine. 

It  is  clear  that  a  fish  may  require  to  get  rid  of  gas  from  its 
swim  bladder,  as  well  as  to  secrete  gas.  If  the  duct  is  open,  there 
is  of  course  no  difficulty  in  getting  rid  of  gas ;  but  it  is  different 


Figure  59. 
Diagram  of  arrangement  of  "oval." 

if  the  duct  is  closed.  The  oxygen  might,  conceivably,  be  secreted 
backwards;  but  often  there  is  a  large  percentage  of  nitrogen  in 
the  gas,  and  there  might  be  trouble  about  this.  It  was  discovered 
by  Jager6  that  in  fishes  with  a  closed  swim  bladder  there  is  an 
oval  window-like  area  on  the  dorsal  side  of  the  swim  bladder 
(Figure  59).  Over  this  area  there  is  nothing  but  a  thin  layer  of 
flattened  cells  between  the  air  of  the  swim  bladder  and  an  under- 
lying layer  containing  a  close  network  of  capillaries.  This  thin 
layer  seems  to  permit  free  diffusion  outwards  of  the  gas  in  the 
swim  bladder.  Assuming  this  to  be  the  case,  the  oxygen  will 
freely  diffuse  into  the  blood  capillaries,  where,  as  already  seen, 

4  Bohr,  Journ.  of  Physwl.,  XV,  p.  499,  1893. 

6  Dreser,  Arch.  f.  Exper.  Pathologie,  XXX,  p.  160. 

e  Jager,  Pfliiger's  Archiv,  XCIV,  p.  65,  1903. 


212 


RESPIRATION 


the  oxygen  pressure  is  very  low.  Nitrogen  and  CO2,  on  the  other 
hand,  will  diffuse  inwards  if  their  partial  pressure  is  less  inside  the 
swim  bladder  than  in  the  blood,  and  outwards  in  the  converse 
case.  The  pressure  of  nitrogen  in  the  blood  is  doubtless  about  79 


Figure  60. 

Section  through  secreting  gland  of  swim  bladder  of  Sciaena  aquila,  showing 
the  epithelial  body  and  underlying  layer  of  capillary  network  (f)  with  gas  bubbles 
distending  the  gas  ducts  of  the  epithelial  body  (Jager). 


Figure  61. 

More  highly  magnified  portion  of  epithelial  body  shown  in 
Figure  60.  A  distended  gas  duct,  with  surrounding  secreting 
cells  (Jager). 


RESPIRATION 


213 


per  cent  of  an  atmosphere,  as  it  is  in  sea  water ;  so  whenever  the 
oxygen  percentage  is  sufficiently  reduced  by  diffusion  to  make 
the  nitrogen  pressure  in  the  swim  bladder  more  than  79  per  cent 
of  an  atmosphere,  the  nitrogen  will  follow  the  oxygen  out  through 
the  "oval" ;  as  will  the  CO2,  and  from  a  similar  cause.  But  Jager 
found  also  that  the  "oval"  can  be  opened  or  closed  by  the  relaxa- 


Figure  62. 

(X  330)  Folds  of  the  swim  bladder  epithelium  of  Gobius  niger. 
C.R.M.,  capillaries  of  the  rete  mirabile.  I.C.C.,  intracellular  capil- 
lary (Woodland). 

tion  or  contraction  of  a  ring  of  unstriped  muscle  surrounding  its 
periphery.  When  this  ring  is  contracted  the  "oval"  is  covered  up 
by  a  layer  of  the  ordinary  lining  membrane  of  the  swim  bladder. 
Thus  not  only  secretion,  but  also  absorption  of  gas  from  the  swim 
bladder,  is  under  complete  physiological  control. 


214 


RESPIRATION 


On  microscopic  section  of  the  wall  of  the  swim  bladder  we  find 
that  at  most  parts  it  is  lined  by  flattened  epithelial  cells  similar  in 
outward  appearance  to  those  covering  the  oval.  At  certain  parts, 
however,  this  flattened  epithelium  passes  into  a  layer  consisting  of 
cubical  or  columnar  epithelial  cells,  and  forming  the  so-called 
"epithelial  body"  (Figures  60,  61),  or  else  a  convoluted  layer  of 
columnar  epithelium  (Figure  62).  In  the  glandular  structure 
ducts  containing  gas  may  be  seen  (Figures  60  and  61)  in  certain 
species  of  fishes,  and  the  gland  is  evidently  an  oxygen-secreting 
gland.  The  true  glandular  structure  was  one  of  Johannes  Miiller's 
many  discoveries  about  glands. 


R.M. 


G.E. 

Figure  63. 

Diagram  of  circulation  in  rete  mirabile  of  eel.  R.M.  rete  mirabile.  G.E.  gland 
epithelium.  Arterioles  and  arterial  capillaries  continuous  lines.  Venules  and  venous 
capillaries  interrupted  lines  (Woodland). 

Beneath  the  glandular  structure  is  a  mass  of  red  blood  vessels, 
forming  a  structure  which  attracted  the  attention  of  anatomists 
hundreds  of  years  ago7  and  came  to  be  known  as  a  rete  mirabile. 
The  arrangement  of  the  blood  vessels  in  this  "red  body"  was  re- 
cently studied  by  Woodland,8  who  established  the  fact  that  the 
rete  mirabile  is  an  arrangement  in  which  the  arterioles  passing 
to  the  gland  break  up  into  capillaries  which  come  into  intimate 
contact  with  corresponding  venous  capillaries  from  the  venules 
coming  from  it  (Figure  63).  What  is  the  significance  of  this? 
The  arrangement  reminds  us  of  that  in  a  regenerating  furnace, 
where  the  heat  carried  away  in  the  waste  gases  is  utilized  to  heat 

T  Redi,  Observations  sur  les  animaux  vivans  contenus  dans  les  animaux  vivans. 
Florence,  1684. 

8  Woodland,  Proc.  Zool.  Soc.  of  London,  p.  183,  1911. 


RESPIRATION 


215 


the  incoming  air.  Nevertheless  it  seems  hardly  probable  that  the 
arrangement  is  for  heat  regeneration.  The  blood  passes  to  the 
gland  with,  presumably,  the  main  physiological  object  of  supply- 
ing oxygen,  and  venous  blood  in  returning  is  already  spent  as 
regards  its  supply  of  oxygen.  Nevertheless  I  think  we  can  now 
suggest  an  explanation.  It  was  discovered  by  Barcroft  and  King9 
that  at  low  temperatures  the  influence  of  CO2  in  expelling  oxygen 
from  haemoglobin  is  much  greater,  relatively  speaking,  than  at  the 
temperature  of  warm-blooded  animals.  The  difference  is  so  great 
as  to  suggest  that  the  dissociation  of  oxyhaemoglobin  in  the  tis- 
sues of  cold-blooded  animals  is  practically  dependent,  not  on  fall 


S.G. 


END 


Figure  64. 

(X  1000).  Transverse  section  through  anterior  end  of  rete  mirabile  of 
Gobius  niger,  showing  the  peculiar  endothelium  (END)  of  the  arterial 
capillaries  (A)  as  compared  with  the  venous  capillaries  (V)  (Woodland). 

of  oxygen  pressure,  but  on  rise  of  CO2  pressure.  It  seems  probable, 
therefore,  that  the  function  of  the  rete  mirabile  is  to  enable  venous 
blood  to  communicate  part  of  its  CO2  to  the  arterial  blood.  The 
effect  of  this  will  be  to  raise  the  CO2  pressure  of  the  blood  sup- 
plied to  the  gland,  and  so  raise  the  oxygen  pressure.  There  may 
be  active  secretion  of  CO2  into  the  arterial  capillaries;  and  this 

9  Barcroft  and  King,  Journ.  of  Physiol.,  XXXIX,  p.  374,  1909. 


2i6  RESPIRATION 

hypothesis  is  supported  by  the  existence  in  the  arterial  capillaries 
of  a  very  peculiar  thickened  endothelium  figured  clearly  by  Wood- 
land (Figure  64). 

Another  very  interesting  case  of  gas  secretion  occurs  in  Arcella 
discoides,  which  is  a  microscopic  unicellular  organism  found  in 
rivers  and  ponds.  It  has  a  more  or  less  transparent  shell,  shaped 
something  like  the  top  of  a  mushroom,  with  an  opening  where  the 
stalk  should  come.  Through  this  opening  it  protrudes  delicate 
pseudopodia,  by  means  of  which  it  can  creep  about  (Figure  65). 


Figure  65. 

Arcella  raising  itself  by  developing  bubbles.  Two  bubbles 
visible  through  shell,  and  pseudopodia  projecting  through 
lower  opening. 

When  a  living  and  healthy  arcella  is  examined  in  a  drop  of  water 
under  the  microscope,  the  presence  of  one  or  more  gas  bubbles 
inside  its  protoplasm  can  at  times  be  observed,  particularly  if  by 
accident  or  design  the  animal  has  been  turned  on  its  back,  with 
the  opening  of  its  shell  upwards.  The  bubbles  of  course  make  the 
animal  lighter,  so  that  it  rises  towards  the  surface  of  the  water, 
and  also  comes  right-side  up,  after  which  they  rapidly  disappear 
again.  The  occurrence  of  these  phenomena  was  described  many 
years  ago  by  Engelmann.  Quite  recently  Dr.  Bles  took  up  the 
subject  again  at  my  suggestion,  as  it  looked  as  if  oxygen  want 
was  in  some  indirect  way  the  real  stimulus  to  the  formation  of  the 
bubbles,  just  as  it  is  (as  we  shall  presently  see)  the  stimulus  to 
oxygen  secretion  in  the  lungs.  He  elicited  the  very  interesting 
fact  that  a  quite  slight  fall  in  the  normal  oxygen  pressure  of  the 
surrounding  water  is  sufficient  to  cause  the  immediate  formation 
of  gas  bubbles  in  the  arcella,  and  thus  cause  it  to  rise  to  where 
presumably  there  is  more  oxygen.  It  seems  probable,  also,  from 
other  observations  made  by  him  later,  that  the  bubbles  which  are 
apt  to  develop  when  the  animal  is  placed  on  its  back  are  a  conse- 
quence of  stimuli  produced  by  internal  want  of  oxygen  owing  to 
increased  oxygen  consumption  during  its  efforts  to  right  itself. 


RESPIRATION  217 

Before  going  further  let  us  try  to  form  some  sort  of  conception 
as  to  what  is  occurring  in  a  gland  cell  during  the  secretion  of 
oxygen.  On  the  side  of  the  cell  next  the  lumen  of  the  duct  we  have 
a  pressure  of  oxygen  which  may  be  1,000  times  as  great  as  on  the 
side  next  the  capillaries ;  and  yet  oxygen  may  be  passing  inwards 
from  the  capillaries  towards  the  duct.  The  cell  is  permeable  to 
oxygen :  for  oxygen  is  passing  through  it.  Yet  the  oxygen  cannot 
be  free  to  dissolve  in  the  ordinary  way  in  the  "protoplasm"  of 
the  cell :  for  if  this  were  the  case  the  oxygen  would  run  backwards 
through  the  cell  like  water  through  a  sieve.  At  a  pressure  of  1 1 5 
atmospheres,  to  go  back  to  our  concrete  example,  100  volumes  of 
water  at  io°C  would  take  up  430  volumes  of  oxygen  (measured 
at  o°  and  760  mm.)  ;  and  if  the  oxygen  were  as  freely  soluble  in 
the  cell  water  as  in  ordinary  water  the  swim  bladder  would  leak 
outwards  at  a  quite  hopeless  rate.  If  we  start  by  looking  upon 
"living  protoplasm"  as  a  mere  solution  and  suspension  of  colloid 
and  other  material,  we  may  as  well  give  up  the  attempt  to  get  any 
insight  whatever  into  even  the  most  rudimentary  physiological 
processes. 

When  we  take  a  broad  general  view  of  the  phenomena  of  life, 
one  of  the  most  fundamental  facts  that  appears  is  that  the  com- 
position of  each  organism  or  part  of  an  organism  is  distinctly 
specific.  The  percentage  and  nature  of  each  of  the  substances 
which  we  can  recover  on  disintegrating  the  living  tissue  are  spe- 
cific ;  and  the  more  we  learn  about  the  nature  of  these  substances 
the  more  clearly  does  this  specific  character  emerge.  It  is  evidently 
no  mere  accident  that  muscle  yields  so  much  potassium,  so  much 
phosphoric  acid,  so  much  water,  and  so  much  of  various  proteins. 
These  substances  must  be  present  in  some  kind  of  combination  in 
the  living  "substance" ;  and  if  so  the  living  substance  cannot  be 
regarded  as  a  mere  solution  of  free  molecules.  The  molecules  are 
in  some  sense  bound,  as  they  are  in  a  solid ;  and  in  so  far  as  this  is 
the  case  the  living  substance  must  in  certain  respects  behave  as  a 
solid,  impervious  to  the  free  passage  of  material  by  diffusion. 
The  layer  of  thin  flattened  epithelium  lining  appears  to  be  gas- 
tight  (to  oxygen  at  least)  except  where  it  covers  the  oval.  At  this 
point  the  layer  allows  gas  to  pass  freely. 

From  this  point  of  view  we  can  understand  why  the  living  cells 
of  the  oxygen-secreting  gland  should  be  gas-tight,  or  nearly  so, 
against  diffusion  backwards,  but  we  have  not  yet  considered  how 
the  gas  passes  forward  through  them  during  secretion;  and  if 


218  RESPIRATION 

"living  material"  behaved  like  an  ordinary  solid  no  such  explana- 
tion would  be  forthcoming.  But  evidently  a  living  cell  does  not 
behave  like  an  ordinary  solid :  for  it  is  constantly  taking  up  and 
giving  off  material,  not  merely  during  secretion,  but  at  every 
moment  of  its  existence.  This  is  evident  from  a  general  considera- 
tion of  the  phenomena  of  nutrition,  and  becomes  still  more  evident 
if  by  altering  the  environment  of  a  cell  we  disturb  the  labile 
balance  between  living  cells  and  their  surrounding  liquids.  In  the 
secretion  of  oxygen  and  many  other  substances,  such  as  urea, 
sugar,  salts,  etc.,  the  substance  taken  up  on  one  side  of  the  cell  is 
given  off  in  the  same  form  on  the  other  side.  In  the  processes  of 
ordinary  nutrition,  on  the  other  hand,  the  taking  up  and  giving 
off  may  be  on  the  same  side  of  the  cell,  and  the  substance  given  off 
may  be  in  a  different  chemical  form  from  that  taken  up.  We  have 
no  reason  to  believe,  however,  that  there  is  any  fundamental  dis- 
tinction between  the  taking  up  and  giving  off  during  ordinary 
nutrition  and  during  secretion.  Nearly  a  century  ago  Johannes 
Miiller,  at  the  end  of  his  famous  memoir  on  secreting  glands,10 
after  pointing  out  that  his  observations  negatived  the  mechanical 
theories  of  secretion  then  current,  suggested  that  secretion  must 
be  regarded  as  a  process  akin  to  growth,  the  only  difference  being 
that  whereas  in  ordinary  growth  the  material  deposited  tends  to 
remain  where  it  is,  in  secretion  it  is  always  being  carried  away 
and  replaced.  Johannes  Miiller's  theory  was  bound  up  with  his 
vitalistic  physiology,  and  the  clue  which  he  was  grasping  at  was 
swept  from  the  hands  of  physiologists  by  the  wave  of  mechanistic 
speculation  which  passed  over  physiology  about  the  middle  of 
last  century.  But  now  that  we  know  from  nearly  a  century  of 
painful  experimental  investigation  what  to  the  genius  of  a  great 
biologist  like  Miiller  was  evident  enough,  that  mechanical  theories 
of  secretion  are  impossible,  we  can  take  up  the  clue  again. 

When  oxygen  (or  indeed  any  other  substance  entering  into 
cell  metabolism)  is  taken  up  on  one  side  of  the  cell,  we  are  led  by 
the  experimental  facts  to  assume  that  the  oxygen  enters  into 
easily  dissociable  chemical  combination.  Were  this  combination 
not  easily  dissociable  we  could  not  understand  why  a  cell  should 
be  so  enormously  sensitive,  as  we  shall  see  later  that  it  is,  to 
changes  in  the  concentration  of  oxygen  and  other  substances  in 
its  immediate  environment.  Now  all  we  know  about  cell  metab- 
olism points  to  the  conclusion  that  the  balance  of  stability  at  any 
one  part  of  the  cell  depends  on  the  balance  of  stability  at  other 

"Johannes  Miiller,  De  Glandularum  Secernentium  Structura  Penitiori,   1830. 


RESPIRATION  219 

parts.  The  taking  up  of  oxygen,  for  instance,  depends  on  a  host 
of  conditions  in  the  environment,  such  as  the  concentrations,  or, 
more  correctly,  the  diffusion  pressures,  of  ions  of  different  sorts, 
and  of  various  other  substances  which  are,  or  may  be,  passing 
into  and  out  of  the  cell.  A  minute  trace  of  pilocarpine,  for  instance, 
will  set  the  oxygen-secreting  cell  violently  taking  up  oxygen  on 
one  side,  and  giving  it  off  on  the  other;  and  probably  we  could 
paralyze  the  oxygen  secretion  at  once  by  reducing  the  concentra- 
tion of  calcium  ions  in  the  cell  environment. 

In  a  secreting  cell  the  rate  of  secretion,  other  conditions  being 
favorable,  depends  on  the  concentration  of  the  dissolved  material 
to  be  secreted.  This  we  can  see  with  the  utmost  clearness  in  the 
case  of  the  kidney  or  intestinal  epithelium.  The  rate  of  secretion 
also  depends  on  the  concentration  of  the  dissolved  material  on 
the  excretory  side,  as  we  can  also  see  in  the  case  of  the  kidney. 
Clear  evidence  on.  this  point  is  summarized  by  Ambard  in  his 
book  La  physiologie  des  reins,  Paris,  1920.  We  are  thus  led 
to  the  conclusion  that  the  stability  of  the  oxygen  combination 
on  one  side  of  the  oxygen-secreting  cell  depends,  other  things 
being  equal,  on  the  stability  of  the  oxygen  combination  at  the 
other  side,  and  that  in  proportion  as  the  oxygen  combination 
at  one  surface  becomes  increased,  the  oxygen  combination  at  the 
opposite  surface  becomes  more  ready  to  release  oxygen  towards 
the  cell  environment.  It  also  seems  probable  that  as  we  proceed 
from  the  absorbing  to  the  secreting  side  of  the  cell,  the  tendency 
to  give  off  oxygen  becomes  greater  and  greater.  A  cell  of  sub- 
stantial thickness  is  therefore  required  to  produce  a  large  differ- 
ence in  oxygen  pressure.  The  combination  which  dissociates  itself 
on  the  excretory  surface  will,  if  the  concentration  of  oxygen  at 
that  surface  is  not  so  high  as  to  stop  the  dissociation,  be  constantly 
resatu  rating  itself  in  part  from  the  combination  lying  deeper  in 
the  cell.  Thus  oxygen  will  travel  from  the  absorbing  to  the  se- 
creting side  of  the  gland  cell,  just  as  urea,  or  sodium,  or  phosphoric 
acid,  will  travel  from  the  absorbing  to  the  secreting  side  of  other 
kinds  of  secreting  cells.  We  can  also  imagine  how,  in  the  course 
of  their  passage,  chemical  transformations  may  occur  in  the 
transported  material,  so  that,  for  instance,  an  intestinal  cell  which 
takes  up  fatty  acid  may  deliver  fat  on  the  other  side,  or  a  cell 
which  takes  up  sugar  may  transform  it  into  fat,  or  amino  acids 
into  proteins,  or  oxygen  into  CO2  and  water,  or  may  perform  any 
of  the  numerous  other  syntheses  or  disintegrations  with  which 
physiologists  are  familiar. 


220  RESPIRATION 

In  the  arcella,  bubbles,  probably  consisting  largely  of  oxygen, 
appear  and  disappear  within  the  cell  body,  according  to  the  ex- 
isting physiological  conditions.  It  seems  probable  that  the  bubbles, 
for  the  development  of  which  a  high  internal  oxygen  pressure 
will  be  needed,  occur  in  interstices  of  the  living  substance,  due  to 
the  presence  of  inclosed  liquid  or  solid  substances.  In  these  inter- 
stices the  gas  pressure  can  rise  up  to  the  point  at  which  it  pro- 
duces disruption  and  bubble  formation.  Gas  bubbles  have  not 
hitherto  been  observed  in  the  cells  of  oxygen-secreting  glands, 
although  certain  microscopic  appearances  have  been  taken  for 
such  bubbles. 

The  well-known  transparent  larva  of  Corethra  possesses  two 
gas  floats :  one  near  the  anterior,  and  the  other  near  the  posterior 
end  of  the  larva.  The  gas  is  enclosed  in  chitinous  bladders  de- 
veloped from  the  tracheal  system  and  partially  rigid,  with  cells 
on  their  external  walls.  If  the  pressure  of  the  water  is  increased 
the  larva  begins  to  sink  owing  to  diminution  in  the  capacity  of 
the  bladders,  but  regains  its  equilibrium  in  two  or  three  minutes; 
and  conversely  if  the  pressure  is  diminished.  This  looks,  therefore, 
like  a  case  of  gas  secretion.  Krogh  showed,  however,  in  a  beautiful 
series  of  experiments10A  that  there  is  no  gas  secretion,  but  secretion 
of  liquid  out  of  or  into  the  bladders,  so  as  to  compensate  for  the 
alteration  in  their  capacity.  The  larva  can  equilibrate  itself  in 
this  way  since  the  bladders  are  partially  rigid.  In  deep  water,  for 
instance,  the  gas  pressure  is  kept  the  same  as  that  of  the  atmos- 
phere, and  hence  much  less  than  that  of  the  surrounding  water. 
The  gas  pressures  inside  and  outside  the  bladders  are  thus  the 
same,  and  simple  diffusion  of  gases  is  not  modified  by  gas  secretion. 

Having  to  some  extent  cleared  our  ideas  by  the  consideration 
of  undoubted  cases  of  gas  secretion,  we  can  now  proceed  to  dis- 
cuss the  evidence  as  to  gas  secretion  by  the  lungs.  As  mentioned 
already,  Ludwig  had  the  idea  (in  which  he  was  right)  that  prob- 
ably something  occurs  in  the  lungs  to  facilitate  the  escape  of  CO2, 
and  possibly  the  absorption  of  oxygen ;  and  this  idea  appeared  in 
the  work  of  some  of  his  pupils.  It  was  a  time  when  physiological 
research  was  very  active  in  Germany;  and  friendly,  or  some- 
times anything  but  friendly,  shots  were  often  exchanged  between 
the  leading  laboratories.  The  Leipzig  idea  was  accordingly  put 
to  the  test  by  Pfliiger  and  his  pupils  at  Bonn,  and  for  the  purpose 
Pfliiger  devised  an  instrument  which  he  called  the  aerotonometer, 
its  object  being  to  measure  the  partial  pressures  or  tensions  of  the 

10A  Krogh,  Skand.  Archiv.  /.  Physiol.,  XXV.  p.  183, 


RESPIRATION  221 

gases  contained  in  venous  and  arterial  blood,  so  that  these  pres- 
sures could  be  compared  with  one  another  and  with  the  corre- 
sponding pressures  in  the  air  of  the  lungs.  The  aerotonometer 
consisted  of  two  tubes  immersed  in  a  water  bath  at  body  tempera- 
ture, and  closed  below  by  a  mercury  seal.  In  one  tube  was  placed 
a  mixture  containing  a  smaller  percentage  of  CO2  and  greater 
percentage  of  oxygen  than  corresponded  to  the  partial  pressures 
expected  in  the  blood ;  and  in  the  other  tube  a  mixture  containing 
a  higher  percentage  of  CO2  and  a  lower  percentage  of  oxygen. 
The  blood  from  the  animal  was  then  allowed  to  trickle  down  the 
inside  of  the  tubes,  so  that  it  should  as  far  as  possible  equalize  its 
gas  tensions  with  those  in  the  tubes,  either  by  taking  up  or  giving 
off  CO2  or  oxygen.  In  a  successful  experiment  the  blood  gave  off 
CO2  and  absorbed  oxygen  in  one  tube,  and  vice  versa  in  the  other, 
so  that  the  gas  pressures  of  the  blood  were  defined  within  narrow 
limits  on  the  analyses  of  the  gases  in  the  two  tubes.  The  sample  of 
lung  air  was  obtained  by  another  ingenious  instrument,  the  "lung 
catheter,"  by  means  of  which  a  bronchus  could  be  blocked  off  and 
a  sample  of  the  gas  in  the  lungs  drawn  off  as  soon  as  the  air  thus 
confined  had  reached  a  constant  composition. 

The  conclusion  drawn  from  the  actual  experiments  by  Pfliiger 
and  his  pupils  was  that  there  was  no  average  difference  in  gas 
pressures  between  the  venous  blood  and  the  air  inclosed  beyond 
the  blocked  bronchus;  and  therefore  no  evidence  of  any  giving 
off  of  CO2  or  absorption  of  oxygen  except  by  simple  diffusion.11 

The  question  was  taken  up  again  by  the  late  Professor  Bohr  of 
Copenhagen,  one  of  Ludwig's  pupils.12  Bohr  improved  the  aeroto- 
nometer, so  that  a  large  stream  of  arterial  blood  could  be  run 
through  it  and  back  to  the  animal,  the  blood  of  which  had  first 
been  rendered  incoagulable  by  injecting  peptone  or  leech  extract. 
He  obtained  the  result  that  while  usually  the  CO2  pressure  in  the 
arterial  blood  is  not  less  than  in  the  alveolar  air,  and  the  oxygen 
pressure  not  greater,  yet  sometimes  this  relation  is  reversed.  From 
these  results  he  concluded  that  active  secretion  of  oxygen  from 
the  lung  air  into  the  blood,  and  of  CO2  from  the  blood  into  the 
lung  air,  may  both  occur.  Owing  to  the  many  possibilities  of 
error  the  results  were  not  very  convincing,  however;  and  Fred- 
ericq13  of  Liege  soon  afterwards  made  a  further  series  of  experi- 

11  Pfli'tger's  Archiv,  IV,  p.  465  ;  VI,  p.  65  ;  VII,  p.  23,  1871-1873. 

12  Bohr,  Skand.  Arch,  of  Physiol.,  p.  236,  1891. 
18  Fredericq,  Arch,  de  Biol.,  XIV,  p.  105,  1896. 


222 


RESPIRATION 


ments,  all  of  which  seemed  to  tell  in  favor  of  Pfliiger's  interpreta- 
tion. 

About  fifteen  years  later  the  aerotonometer  was  greatly  im- 
proved by  Krogh,  who  was  then  Bohr's  assistant.  He  very  greatly 
diminished  the  volume  of  air  exposed  to  the  blood  in  the  aeroto- 
nometer, thus  rendering  it  far  quicker  in  its  action ;  and  ultimately 
he  succeeded  in  working  with  a  single  bubble  of  air,  round  which  a 
stream  of  blood  could  play,  the  bubble  being  afterwards  analyzed 
with  the  help  of  a  graduated  capillary  tube  into  which  it  could  be 
sucked  up  and  measured  before  and  after  its  CO2  and  oxygen 
had  been  removed  by  suitable  reagents. 


Figure  66. 

Krogh's  micro-aerotonometer,  showing  inlet  and  outlet 
for  blood,  lower  part  of  measuring  tube,  and  air  bubble. 

Before  his  death  Bohr  published  some  experiments  made  with 
Krogh's  aerotonometer,  and  apparently  showing  distinctly  that 
the  pressure  of  CO2  in  the  venous  blood  could  be  less  than  in  the 
expired  air,  although  CO2  was  being  given  off  in  the  lungs ;  and 
that  the  arterial  CO2  pressure  could  also  be  less  than  that  of  the 
expired  air.  Krogh  himself,  however,  took  the  view  that  there 
were  errors  in  these  experiments,  and  published,  along  with  M. 
Krogh,  the  results  of  a  careful  series  of  experiments  on  animals 
under  conditions  which  were  much  more  nearly  normal  than  in 


RESPIRATION  223 

any  previous  experiments.14  The  arterial  oxygen  pressures  were 
always  very  distinctly  below  the  oxygen  pressures  at  the  same 
time  in  the  alveolar  air;  while  the  arterial  CO2  pressures  were 
sensibly  equal  to  those  in  the  alveolar  air.  There  was  never  any 
approach  to  excess  of  arterial  over  alveolar  oxygen  pressure,  or 
of  alveolar  over  arterial  CO2  pressure,  even  when  these  pressures 
were  varied  considerably  by  altering  the  composition  of  the  in- 
spired air.  Krogh,  therefore,  rejected  Bohr's  conclusions  that 
there  is  active  secretion  of  oxygen  or  CO2  in  the  lungs,  and  con- 
cluded in  favor  of  Pfliiger's  view  that  the  exchange  of  gases  in 
the  lungs  is  entirely  due  to  diffusion.  The  following  table  shows 
the  results  of  a  typical  experiment  in  which  the  alveolar  oxygen 
pressure  was  varied  during  the  experiment,  the  alveolar  air  and 
blood  samples  being  taken  nearly  simultaneously. 


TIME 

TENSION  OF  CO2  IN 

TENSION  OF 

OXYGEN  IN 

Alveoli 

Blood 

Alveoli 

Blood 

1.36-43 

3-6 

3.7 

12.  0 

IO.O 

2.  10-12 

3.o 

3-5 

18.0 

15.0 

3-03-    3-07 

2-5 

2-5 

12.0 

ii-5 

Before  following  this  long  controversy  further,  I  should  like 
to  point  out  a  fallacy  in  the  interpretation  of  the  aerotonometer 
results.  The  conclusion  of  Pfliiger  that  diffusion  alone  explains 
the  giving  off  of  CO2  in  the  lungs  was  wholly  fallacious,  as  has 
already  been  shown  in  Chapter  V.  The  oxygen  reaching  the 
blood  in  the  lungs  helps  to  drive  out  CO2  ,*  and  under  certain  con- 
ditions which  are  very  apt  to  occur  during  physiological  experi- 
ments on  animals,  and  may  easily  be  produced  in  man,  the  venous 
CO2  pressure  may  be  lower  than  that  of  the  alveolar  air,  although 
no  secretion  at  all  may  be  occurring.  In  the  lung-catheter  experi- 
ments the  oxygen  supply  to  the  lungs  was  blocked  off,  so  that  the 
blood  could  not  take  up  oxygen.  As  a  consequence  the  CO2  pres- 
sure in  the  confined  air  must  have  been  considerably  lower  than  if 
oxygen  had  been  present.  In  reality  Ludwig  was  right,  and 
Pfliiger  was  wrong.  This  source  of  fallacy  does  not  in  any  way 
invalidate  Krogh's  conclusion  that  the  arterial  CO2  pressure  is 
not,  under  normal  conditions,  lower  than  the  alveolar  CO2  pres- 
sure. I  think  this  conclusion  is  correct ;  and  it  agrees,  as  he  points 
out,  with  all  the  indications  given  by  the  work  of  Priestley  and 

14  A.  and  M.  Krogh,  Skond.  Arch.  f.  Physwl.,  XXXII,  p.  179,  I9io. 


224  RESPIRATION 

myself  on  the  regulation  of  breathing  in  accordance  with  the 
alveolar  CO2  pressure. 

When  Bohr's  original  experiments  on  the  question  of  secretion 
by  the  lungs  were  published  in  1891,  I  was  just  beginning  the 
serious  study  of  mine  gases  and  the  physiological  effects  of  vitiated 
air;  and  his  results  interested  me  greatly.  A  year  or  two  later 
Lorrain  Smith  and  I  made  a  visit  of  several  weeks  to  Copenhagen, 
and  carried  out  some  research  work  in  the  laboratory  under 
Bohr's  direction,  thus  learning  a  great  deal  which  we  could  not 
have  learned  in  England  about  existing  methods  of  blood-gas 
investigation,  and,  far  more  important,  getting  into  personal 
touch  with  Bohr  himself.  I  should  like  to  take  this  opportunity  of 
saying  how  much  we,  and  indirectly  other  physiologists  in  Great 
Britain  and  America,  have  owed  to  Bohr  and  the  Copenhagen 
School  of  physiologists. 

The  difficulties  of  the  aerotonometer  method  of  determining  the 
oxygen  pressure  of  arterial  blood  were  very  evident,  and  I  cast 
about  in  my  mind  for  some  better  method.  Soon  afterwards  I 
began  investigating  the  action  of  carbon  monoxide  in  mines,  and 
the  results  of  this  investigation,  and  the  colorimetric  method  of 
blood  examination,  which  I  worked  out  during  the  investigation, 
suggested  a  new  means  of  attacking  the  problem  which  Ludwig 
had  originally  suggested. 

The  general  principle  of  this  method  has  already  been  ex- 
plained in  Chapter  IV,  and  depends  on  the  fact  that  within  wide 
limits  the  relative  proportions  in  which  haemoglobin  is  shared 
between  oxygen  and  CO  are  proportional  to  the  relative  partial 
pressures  of  the  two  gases  when  allowance  is  made  for  their  rela- 
tive affinities  for  the  haemoglobin.  Hence  if  the  proportions  in 
which  oxygen  and  CO  are  shared  in  the  haemoglobin  of  the 
blood  when  equilibrium  is  established  are  known,  as  well  as  the 
pressure  of  CO,  the  pressure  of  oxygen  can  be  calculated.  To 
measure  the  oxygen  pressure  in  the  arterial  blood  it  is  therefore 
only  necessary  to  allow  a  man  or  animal  to  breathe  a  constant  small 
percentage  of  CO  until  absorption  of  CO  stops,  owing  to  a  balance 
having  been  struck  between  oxygen  pressure  and  CO  pressure  in 
the  blood  passing  through  the  lung  alveoli.  The  percentage  satu- 
ration of  the  haemoglobin  with  CO  is  then  determined,  and  the 
arterial  oxygen  calculated  from  a  knowledge  of  the  relative  affini- 
ties of  the  two  gases  for  haemoglobin,  as  determined  outside  the 
body. 

The  method  seemed  simple  in  principle,  but  it  turned  out  to 


RESPIRATION  225 

be  as  full  of  pitfalls  in  practice  as  the  use  of  the  blood  pump, 
aerotonometer,  or  spectrophotometer.  What  misled  us  most  were : 
(i)  the  assumption  that  Hiifner's  oxyhaemoglobin  dissociation 
curve,  then  and  for  many  years  later  quoted  in  every  textbook, 
was  at  least  approximately  correct;  (2)  the  assumption  that  all 
haemoglobin  is  alike  as  regards  its  relative  affinities  for  oxygen 
and  CO;  (3)  ignorance  at  first  of  the  powerful  action  of  bright 
light  on  the  dissociation  of  CO  haemoglobin,  and  of  the  influence 
of  temperature;  (4)  failure  at  first  to  realize  how  long  it  takes 
to  saturate  blood  or  blood  solution  outside  the  body  with  air  con- 
taining low  percentages  of  CO.  There  were  probably  also  some 
errors  in  the  colorimetric  titrations,  owing  chiefly  to  our  not  taking 
precautions  which  subsequent  experience  showed  to  be  necessary, 
against  decomposition  of  blood  solutions  during  long  experiments. 
The  first  experiments  were  made  by  Lorrain  Smith  and  my- 
self15 on  men,  the  subject  of  the  experiment  going  through  the 
lengthy  process  of  breathing  air  containing  a  definite  small  per- 
centage of  CO,  until  absorption  of  CO  ceased,  as  shown  by  the 
analyses  of  blood  samples.  The  results  led  us  to  the  conclusion 
that  the  normal  resting  arterial  oxygen  pressure  was  considerably 
above  that  of  the  alveolar  air;  and  corrections,  made  afterwards 
for  the  causes  of  error  just  referred  to  caused  this  conclusion  to 
stand  out  still  more  clearly.  Subsequent  experience  leads  me  to 
the  conclusion  that  we  had  become  acclimatized  more  or  less  to 
want  of  oxygen  by  frequently  breathing  CO,  so  that  at  the  time 
we  were  no  longer  ordinary  normal  subjects.  We  were  at  any 
rate  breathing  with  complete  impunity  a  percentage  of  CO  which 
would  under  ordinary  circumstances  cause  very  unpleasant  symp- 
toms. On  trying  the  next  year  and  once  or  twice  subsequently  to 
repeat  one  of  the  experiments,  we  were  surprised  to  find  that  the 
former  percentages  were  too  high  for  us,  and  we  suspected  that 
there  must  have  been  some  error  about  the  percentages  breathed 
in  the  first  series  of  experiments.  On  reconsidering  the  matter  I 
cannot  see  how  there  could  have  been  an  error  about  the  per- 
centages breathed.  It  now  seems  practically  certain  that  we  had 
become  acclimatized,  and  had  consequently  developed  during 
the  experiments  a  considerably  higher  arterial  oxygen  pressure 
than  normal  persons  would  have  had,  or  than  we  ourselves  would 
have  had,  if  we  had  not  absorbed  so  much  carbon  monoxide  as  in 
the  experiments,  and  thus  become  somewhat  short  of  oxygen. 

"Haldane  and  Lorrain  Smith,  Journ.  of  Phystol.,  XX,  p.  497,  1896. 


226  RESPIRATION 

Our  next  experiments16  were  on  various  small  animals — 
chiefly  mice.  Small  animals  are  specially  convenient,  as  their 
blood  becomes  saturated  within  a  few  minutes  to  its  maximum 
extent  for  any  percentage  of  CO  in  the  air.  These  experiments 
again  gave  an  apparently  higher  oxygen  pressure  in  the  arterial 
blood  than  in  the  alveolar  air.  When  the  percentage  of  CO  was  in- 
creased, so  that  the  animals  began  to  show  symptoms  of  consid- 
erable oxygen  want,  the  difference  between  arterial  and  alveolar 
oxygen  pressure  became  much  greater.  On  the  other  hand,  when 
the  animals  were  breathing  a  mixture  of  oxygen  and  CO  there 
was  still  a  large  apparent  excess  of  arterial  over  alveolar  oxygen 
pressure.  This  result  was  a  great  disappointment  to  us,  as  we  had 
hoped  that  when  oxygen  was  breathed,  active  secretion  of  oxygen 
inwards  would  cease.  The  fact  that  it  apparently  did  not  do  so 
ought  to  have  aroused  our  suspicions  of  the  correctness  of  the 
measurements.  The  phenomena  observed  when  the  oxygen  per- 
centage, or  the  barometric  pressure,  was  diminished,  led  us,  apart 
from  the  measurements,  to  conclude  that  secretion  of  oxygen  in- 
wards became  more  active;  but  in  our  measurements  of  oxygen 
pressure  we  were  depending  on  the  substantial  correctness  of 
Hiifner's  dissociation  curve;  and  when  this  curve  was  subse- 
quently found  to  be  totally  incorrect  our  measurements  had  also 
to  be  abandoned  as  incorrect. 

During  the  next  few  years  knowledge  as  regards  the  dissocia- 
tion of  haemoglobin  had  greatly  increased,  thanks  to  the  work  of 
Bohr,  Zuntz  and  Loewy,  Barcroft,  and  others,  as  well  as  our  own 
work,  as  described  in  Chapter  IV.  Douglas  and  I  now  took  up  the 
old  subject  again,  but  with  far  more  complete  knowledge  of  the 
material  we  were  dealing  with.17  Dr.  Krogh  had  also  kindly  in- 
formed me  in  a  letter  of  some  experiments  he  had  made  (subse- 
quently published)18  showing  that  in  the  blood  of  a  rabbit  the 
relative  affinities  for  haemoglobin  of  oxygen  and  CO  were  dif- 
ferent from  those  in  the  ox ;  and  we  found,  as  already  mentioned 
in  Chapter  IV,  that  this  is  not  only  so  for  different  classes  of  ani- 
mals, but  also,  and  in  a  most  marked  degree,  for  different  indi- 
viduals of  the  same  species. 

We  therefore  had  to  modify  the  method.  Each  animal  was  ex- 
posed for  a  sufficient  time  to  a  definite  percentage  of  CO  in  a 
bottle,  and  then  drowned  in  situ.  Some  of  its  blood  was  then 

19  Haldane  and  Lorrain  Smith,  Journ.  of  Physiol.,  XXII,  p.  231,  1897. 
"  Douglas  and  Haldane,  Journ.  of  Physiol.,  XLIV,  p.  305,  1912. 
"Krogh,  Skand.  Arch.  /.  Physiol.,  XXXII,  p.  255,   1910. 


RESPIRATION 


227 


placed,  undiluted  and  at  body  temperature,  in  the  saturator,  and 
thoroughly  saturated  in  presence  of  some  of  the  same  mixture  of 
air  and  CO  that  the  animal  had  been  breathing.  The  percentage 
saturations  with  CO  of  the  haemoglobin  in  the  blood  taken 
straight  from  the  animal,  and  in  that  from  the  saturator,  were 
then  determined,  and  the  arterial  oxygen  pressure  calculated  in 
the  usual  way.  The  following  table  shows  the  results. 


Duration 

Percentage  saturation  Arterial  oxygen 

of  exp.  in 

of  haemoglobin 

pressure  in  per- 

Animal used 

Percentage 

minutes 

with  CO 

centage  of  the  ex- 

of  CO 

s~^ 

*^^  -•*      • 

^        existing 

In  vivo 

In  vitro       atmosphere* 

Mouse 

.Ol6 

60 

26.2 

17.2 

12.2 

» 

.0165 

50 

26.7 

19-5 

13.9 

» 

.018 

45 

26.0 

I8.5 

13-5 

» 

.019 

33 

19.7 

12-5 

I2.I 

» 

.025 

43 

25.6 

I7.6 

13-0 

» 

.046 

40 

29.1 

22.7 

15.0 

» 

•053 

40 

37-7 

30.2 

16.2 

M 

.IOO 

32 

45-0 

43-0 

19-3 

» 

.129 

3i 

56.4 

56.3 

20.8 

» 

.198 

— 

57-6 

56.5 

2O.O 

9) 

.213 

13 

59-1 

75-5 

44-Tt 

» 

.244 

12 

67.3 

71.7 

25-7t 

» 

•255 

60 

60.1 

62.8 

23-3 

» 

.260 

25 

67.0 

64.7 

18.9 

» 

.262 

20 

66.4 

73-7 

28.2 

H 

•275 

25 

66.5 

76.9 

35-9 

Rabbit 

.029 

140 

28.0 

18.7 

12.4 

Same  rabbit 

.191 

ISO 

58.2 

56.0 

19.1 

*  Calculated  without  reduction  for 

aqueous 

vapor  in  the 

alveolar  air. 

f  Mouse  died. 

On  looking  down  this  table  it  will  be  seen  that  as  long  as  the 
percentage  of  CO  did  not  exceed  about  .03  per  cent,  or  the  per- 
centage saturation  of  the  blood  did  not  go  over  about  28  per  cent, 
the  arterial  oxygen  pressure  was  only  about  that  of  the  alveolar 
air,  assuming  that  the  alveolar  air  of  a  mouse  has  about  the  same 
composition  as  human  alveolar  air.  But  as  the  percentage  of  CO 
in  the  air,  or  the  percentage  saturation  of  the  blood,  rose,  the 
arterial  oxygen  pressure  rose,  first  to  about  that  of  the  inspired 
air,  and  then,  in  most  cases,  far  above  it — sometimes  to  double. 


228  RESPIRATION 

We  then  repeated  the  old  experiments  with  oxygen  which  had 
disappointed  Lorrain  Smith  and  me  so  much.  The  results  were 
as  follows: 


EXPERIMENTS  WITH  MIXTURES  OF  OXYGEN  AND  CO  ON  MICE 

Percentage  saturation       Oxygen  pressure  in  percentage 
Duration    of  haemoglobin  with  CO     of  the  existing  atmosphere* 

Percentage    of  exp.  in             ^        "     _  ^~         f 

* 

of  CO           •minutes        In  vivo          In  vitro  Arterial  blood. 

Inspired  air 

0.16             30             31.3             29.6 

77-4 

83.9 

0.61             30             57.0             54.6 

66.6 

73-5 

I.I5                 30                 71.4                 70.8 

83.1 

85.6 

1.47                 30                 69.0                 75.0 

96.3 

71-5 

*  Calculated  without  reduction  for  aqueous  vapor. 

It  will  be  seen  that  as  long  as  the  saturation  of  the  blood  with 
CO  did  not  exceed  about  60  per  cent,  the  arterial  oxygen  pressure 
was  about  7  per  cent  below  that  of  the  inspired  air,  just  as  the 
alveolar  oxygen  pressure  would  be.  With  over  60  per  cent  satura- 
tion, however,  the  animals  began  to  suffer  from  oxygen  want, 
and  the  arterial  oxygen  pressure  went  just  as  high  above  that  of 
the  inspired  air  as  in  animals  breathing  ordinary  atmospheric 
air.  The  old  experiments  were  wrongly  calculated,  because  the 
relative  affinities  of  haemoglobin  for  oxygen  and  CO  are  on  an 
average  different  in  mouse  blood  from  what  they  are  in  human 
blood  or  in  the  ox  blood  which  we  then  took  as  a  fixed  standard. 
This  led  us  to  calculate  the  arterial  oxygen  pressure  about  50  per 
cent  too  high  in  both  the  ''normal"  and  the  oxygen  experiments. 
Moreover  the  "normal"  experiments  were  not  normal,  since  the 
percentage  saturations  of  the  blood  were  about  40  per  cent,  and 
therefore  too  high  to  give  normal  results  such  as  those  of  the  first 
five  experiments  in  the  previous  table.  If  one  recalculates  the 
average  results  of  the  old  experiments  in  the  light  of  this  new 
knowledge  they  give  just  the  same  result  as  the  new  experiments. 

The  general,  and  absolutely  sharp  and  definite,  result  of  these 
experiments  is  that  with  very  low  percentages  of  CO  there  was 
no  evidence  of  active  secretion  of  oxygen  inwards,  but  that  with 
higher  percentages  of  CO  there  was  perfectly  clear  evidence  of 
active  secretion.  This  active  secretion  began  to  show  itself  as  soon 
as  the  CO  percentage  was  sufficient  to  cause  symptoms  of  CO 
poisoning,  which  symptoms,  as  shown  in  Chapter  VII,  are  simply 


RESPIRATION  229 

those  of  oxygen  want :  moreover  the  secretion  did  not  appear  if 
oxygen  was  breathed  along  with  the  CO,  until  a  much  higher 
saturation  of  the  blood  with  CO  was  reached.  Pure  oxygen,  as 
already  shown  in  Chapter  VII,  provides  a  certain  supply  of  dis- 
solved oxygen  to  the  blood  independently  of  the  oxygen  carried  by 
the  haemoglobin,  and  thus  prevents,  to  a  large  extent,  the  oxygen 
want  which  would  otherwise  be  caused  by  the  CO. 

Now  the  oxygen  want  is  in  the  tissues,  and  not  in  the  lungs. 
Hence  the  stimulus  to  secretion  originates  in  the  tissues.  This 
stimulus  is  almost  certainly  something  carried  by  the  blood  from 
the  oxygen-starved  tissues  to  the  lungs  or  central  nervous  system. 
One  might  perhaps  suppose  that  whenever  the  respiratory  center 
is  excited,  nervous  impulses  pass  down  secretory  fibers  in  the  vagus 
nerve  and  excite  secretion  in  the  lungs.  Lorrain  Smith  and  I  tested 
this  hypothesis,  and  found  that  when  the  respiratory  center  was 
excited  by  excess  of  CO2  there  was  not  the  slightest  rise  in  the 
arterial  oxygen  pressure.  Hence  the  secretion  has  no  direct  con- 
nection with  the  ordinary  activity  of  the  center  in  producing 
respiratory  movements;  and  the  stimulus  to  secretion  is  not  a 
hydrogen  ion  stimulus. 

We  also  made  a  series  of  determinations  on  man.  In  view  of 
the  results  of  the  mouse  experiments  we  were  anxious  to  work 
with  low  percentages  of  CO ;  but  if  we  had  used  the  old  method 
which  Lorrain  Smith  and  I  had  employed,  it  would  have  taken 
so  long  before  equilibrium  was  reached  between  the  CO  in  the 
air  and  that  in  the  blood  that  our  experiment  could  hardly  have 
been  completed  during  winter  daylight.  We  therefore  adopted 
the  course  of  quickly  absorbing  as  much  CO  as  would  saturate 
the  blood  to  the  desired  extent,  and  then  breathing  in  and  out  of 
a  small  air  space,  in  which  the  oxygen  and  CO2  percentage  was 
kept  constant.  Under  these  conditions  CO  must,  of  course,  be 
given  off  into  the  air  of  the  space,  and  as  this  air  is  breathed  again 
and  again,  equilibrium  between  the  CO  in  the  air  and  that  in  the 
blood  must  establish  itself  very  quickly.  The  method  finally 
adopted  was  as  follows  (see  Figure  67). 

The  subject,  wearing  a  nose  clip,  breathes  through  the  mouth- 
piece A,  inhaling  through  the  inspiratory  valve  B,  and  expiring 
through  the  valve  C.  The  expired  air  passes  through  a  rubber 
pipe  of  large  caliber  to  the  tin  vessel  D,  which  is  filled  with  small 
fragments  of  solid  caustic  soda,  and  is  made  of  such  a  size  (di- 
ameter 23  cms.,  depth  12  cms.)  that  the  whole  of  the  carbonic 
acid  in  the  expired  air  is  effectively  removed.  Another  rubber 


230 


RESPIRATION 


pipe  leads  the  outgoing  air  current  from  D  to  the  bottle  E  of  12 
liters  capacity,  which  is  connected  by  another  pipe  with  the  in- 
spiratory  valve  B.  The  entrance  and  exit  pipes  of  E  are  so  ar- 
ranged that  the  incoming  air  current  is  directed  to  the  bottom  of 
the  bottle,  while  the  subject  inhales  air  from  the  top.  The  arrows 


r  "= 


Figure  67. 
Apparatus  for  determining  the  arterial  oxygen  pressure  in  man. 

indicate  the  direction  of  the  air  current  caused  by  the  subject's 
respiration  in  the  main  circuit.  Two  side  pipes  lead  into  the  rubber 
pipe  connecting  D  with  E.  One  of  these,  G,  is  of  large  bore  and 
short,  and  is  connected  with  a  vulcanized  rubber  gas  bag  of  con- 
siderable size,  such  as  is  utilized  on  Clover's  ether  apparatus. 
This  bag  serves  only  to  accommodate  each  expiration,  as  the  rest 
of  the  apparatus  is  indistensible,  and  at  the  end  of  inspiration 
the  bag  collapses  entirely.  The  other  side  pipe  F  serves  for  the 
admission  of  oxygen.  The  oxygen  supply  is  so  arranged  that  oxy- 
gen enters  the  main  air  circuit  automatically  to  fill  up  the  defi- 
ciency caused  by  the  absorption  of  oxygen  by  the  subject  at  each 
breath.  It  is  essential  in  a  closed  system  of  small  size  that  the 
oxygen  supplied  shall  be  pure;  the  small  amount  of  nitrogen 
contained  in  ordinary  cylinder  oxygen  renders  its  use  inadmis- 
sible. We  therefore  in  all  the  later  experiments  used  oxygen 
made  by  the  action  of  water  on  "oxylith"  in  the  generator  H.  The 
current  of  oxygen  is  controlled  by  the  tap  at  the  top  of  the  gen- 
erator, and  passes  along  a  pipe  past  a  blow-off  valve  to  air  J, 
through  a  small  gas  meter  K  and  thence  through  a  water  valve 


RESPIRATION  231 

M  to  enter  the  main  air  circuit  at  F.  The  height  of  the  water  above 
the  orifice  of  the  pipe  in  M  is  about  2  mm.  greater  than  in  J,  and 
the  oxygen  therefore  passes  out  to  air  through  the  valve  J  unless 
a  slight  negative  pressure  is  set  up  in  the  main  air  circuit,  when 
it  will  pass  by  preference  through  M.  Such  a  negative  pressure 
obtains  in  the  main  air  circuit  only  at  the  end  of  an  inspiration, 
and  depends  upon  the  fact  that  the  whole  volume  of  air  in  the  cir- 
cuit is  diminished  by  the  amount  of  oxygen  absorbed  at  the  last 
breath  of  the  subject,  as  the  carbonic  acid  expired  is  removed.  The 
meter  records,  therefore,  the  actual  oxygen  consumption  by  the 
individual.  Interposed  between  the  meter  and  the  valve  M  is  a 
small  rubber  bag  L,  such  as  is  used  in  a  small  sized  football.  This 
serves  as  a  reservoir  for  the  oxygen,  and  enables  a  free  and  sudden 
supply  to  be  drawn  into  the  air  circuit.  Without  this  it  would  be 
necessary  to  run  the  oxygen  from  the  generator  at  an  excessive 
and  wasteful  rate,  and  the  slight  resistance  of  the  meter  might 
be  felt.  In  practice  the  oxygen  supply  is  so  adjusted  that  it  is  just 
escaping  continuously  to  air  through  J,  so  as  to  insure  that  the  bag 
L  is  filled  to  constant  pressure;  otherwise  the  readings  of  the 
meter  will  not  accurately  represent  the  oxygen  consumption. 

A  Haldane  gas  analysis  apparatus  N  is  attached  directly  to  the 
air  pipe  leading  from  the  bottle  E  to  the  inspiratory  valve,  so  that 
samples  of  the  inspired  air  may  be  withdrawn  at  intervals  during 
the  experiment  for  analysis.  The  extremity  of  a  vacuous  gas 
sampling  tube  O  is  inserted  into  the  pipe  between  the  expiratory 
valve  and  the  caustic  soda  tin,  not  far  from  the  former,  for  the 
purpose  of  obtaining  a  sample  of  alveolar  air  by  Haldane  and 
Priestley's  method.  By  means  of  the  tap  P,  connected  with  the 
laboratory  water  supply,  a  large  volume  of  air  can  be  displaced 
from  the  bottle  E  through  the  pipe  R,  and  used  for  filling  satu- 
rating vessels,  etc.  Before  each  experiment  the  apparatus  is  tested 
for  air-tightness  by  disconnecting  the  oxygen  supply  pipe  at  F 
and  substituting  a  water  manometer  for  it,  and  then  producing  a 
positive  or  negative  pressure  by  blowing  in  air  or  sucking  it  out 
through  the  mouthpiece.  The  whole  apparatus  is  readily  blown 
out  with  fresh  air  by  disconnecting  the  return  air  pipe  from  the  in- 
spiratory valve  and  blowing  through  the  mouthpiece  with  a  pair 
of  bellows. 

We  found  that  the  percentage  of  oxygen  in  the  air  in  the  ap- 
paratus falls  by  about  0.8  per  cent  during  the  first  five  minutes  of 
an  experiment,  doubtless  owing  to  the  rise  of  temperature  caused 
by  the  breathing,  which  will  hinder  the  entrance  of  oxygen.  After 


232  RESPIRATION 

this  the  oxygen  percentage  shows  oscillations,  which  however  do 
not  exceed  I  per  cent.  Such  oscillations  are  unavoidable,  seeing 
that  the  oxygen  supply  must  be  influenced  in  this  method  by  the 
depth  of  the  individual  breaths :  the  percentage  could  only  re- 
main absolutely  constant  if  the  depth  of  breathing  was  itself 
constant.  For  the  same  reason  the  oxygen  consumption  should  not 
be  determined  over  a  shorter  period  than  five  minutes. 

One  great  advantage  of  this  apparatus  is  that  it  is  very  easy 
to  subject  oneself  to  atmospheres  containing  different  percentages 
of  oxygen  by  means  of  it.  To  obtain  an  atmosphere  poor  in  oxygen 
all  that  is  necessary  is  to  uncouple  the  oxygen  supply  from  the 
valve  M  and  breathe  into  the  apparatus.  Air  now  enters  through 
F  instead  of  oxygen,  and  breathing  is  continued  until  analysis  of 
the  inspired  air  shows  that  the  required  degree  of  oxygen  de- 
ficiency has  been  produced.  If  the  oxygen  supply  is  now  reestab- 
lished the  artificial  atmosphere  produced  will  remain  constant. 
To  obtain  an  atmosphere  rich  in  oxygen,  the  gas  may  be  blown  in 
through  the  orifice  for  the  alveolar  air  sampling  tube,  leaving  the 
mouthpiece  free  for  the  escape  of  the  displaced  air  from  the  re- 
turn air  pipe. 

The  total  volume  of  the  air  in  our  apparatus  is  about  15  liters, 
and  we  may  therefore  presume  that  the  whole  of  it  goes  through 
the  alveoli  of  a  resting  adult  subject  in  three  minutes.  We  have 
on  a  number  of  occasions  breathed  into  the  apparatus  for  an 
hour  with  the  greatest  comfort,  the  percentage  of  oxygen  mean- 
while varying  only  within  the  limits  mentioned  above. 

The  time  during  which  the  subject  breathed  into  the  respiration 
apparatus  in  our  experiments  has  varied  on  different  occasions 
from  twenty  minutes  to  one  hour.  So  far  as  we  could  ascertain  the 
shorter  time  was  sufficient  to  establish  equilibrium  of  concentra- 
tion of  the  carbon  monoxide  in  the  blood  and  in  the  air  breathed, 
though  we  have  as  a  rule  adopted  a  period  in  excess  of  this"  as  a 
matter  of  precaution.  In  our  earlier  experiments  we  passed  about 
2  cc.  of  CO  into  the  air  in  the  respiration  apparatus  before  begin- 
ning to  breathe  into  it,  in  order  that  the  percentage  of  this  gas 
present  at  the  start  might  approximate  to  its  final  value.  As  this 
procedure  had  no  influence  on  the  result  of  the  experiment  we 
gave  it  up,  and  the  respiration  apparatus  thereafter  always  con- 
tained air  free  from  CO  at  the  commencement  of  the  experiment. 

Analyses  of  the  inspired  air  were  made  several  times  during  the 
course  of  the  experiment,  as  it  was  naturally  important  for  our 
purpose  that  the  composition  of  the  inspired  air  should  show  none 


1  1 

^-Cj           *w 
^            VA 

-^      *•> 

.^     ^ 

K  •§     ^ 

f  >8 

*cX     S 

-S  ^  § 

K  "**    tv 

^  -^"S 

"3    «    5 

Q    »    Q 

**! 

5  *  5 

5'  !*» 

ion    3  U 

^       ?  s  ^ 

*         §  " 

'S      5  •*  ^ 

o       oil 

^.    o^loi 

14.2 

(104.4) 

I4.I 

91.6 

12.8 

102.7 

13.2 

93.4    •    Normal  oxygen 

16.2 

1  1  0.8       atmosphere.  Rest. 

14.45 

(92.0) 

\      13-9 

98.9  J 

Mean 

99.1 

:      21.7 

100.2          High  oxygen 

:      23.i 

98.5       atmosphere.   Rest. 

6.9 

H5.4  ' 

8.5 

1  2  1  .6           Low  oxygen 

8.2 

128.1       atmosphere.  Rest. 

6.2 

112.  1 

16.0 

124.8       Moderate  work 

with  one  arm. 

19.9 

131.7  ]                                   Normal 

20.9 

135.0   \      Severe  work       '  oxygen. 

14.9 

128.0   \    with  one  arm. 

24.8 

128.0  J 

15.1 

147.6       Moderate  work 

with  one  arm. 

Low  oxygen. 

RESPIRATION  233 

but  minimal  variations.  Shortly  before  the  close  of  the  experi- 
ment a  sample  of  blood  was  withdrawn  from  the  subject's  ringer 
into  a  capsule,  and  defibrinated  with  a  platinum  wire.  Five-hun- 
dredths  cc.  of  this  blood  was  then  introduced  into  the  saturating 
vessel  in  the  manner  described  in  our  paper.  Immediately  after- 
wards two  further  small  samples  of  blood  were  taken  from  the 
subject's  fingers — as  a  rule  one  from  each  hand — the  blood  being 
received  into  small  test  tubes  quite  full  of  water,  which  were  im- 
mediately corked.  These  samples  served  for  the  colorimetric 
determination  of  the  degree  of  saturation  of  the  blood  with  carbon 
monoxide.  A  last  sample  of  the  inspired  air  was  then  taken,  and 
a  sample  of  the  alveolar  air.  Breathing  into  the  apparatus  was 
continued  for  about  two  minutes  in  case  the  composition  of  the 
air  in  the  respiration  apparatus  had  been  altered  by  the  deep  ex- 
piration necessary  to  afford  the  alveolar  air  sample :  some  car- 
bonic acid,  for  instance,  might  have  got  through  the  caustic  soda 
tin.  The  experiment  then  terminated,  and  the  mouthpiece  of  the 
respiration  apparatus  was  at  once  closed.  The  saturating  vessel 
containing  the  blood  was  as  soon  as  possible  filled  by  displacement 
with  some  of  the  air  remaining  in  the  respiration  apparatus,  which 
was  expelled  for  this  purpose  from  the  bottle  E  by  the  arrange- 
ment indicated  at  P  and  R.  While  the  saturating  vessel  was  being 
rotated  in  the  water  bath  at  38°  the  determination  of  the  degree 
of  saturation  with  carbon  monoxide  of  the  samples  taken  from 
the  ringers  was  proceeded  with.  During  this  time  also  the  analyses 
of  the  alveolar  air,  and  air  from  the  respiration  apparatus,  were 
completed  and  when  necessary  the  analysis  of  a  sample  from  the 
saturating  vessel.  After  the  saturating  vessel  had  been  rotated  for 
half  an  hour  or  more,  it  was  removed  from  the  water  bath  and 
the  degree  of  saturation  with  carbon  monoxide  of  the  blood  con- 
tained in  it  was  determined.  All  the  data  for  calculating  the 
oxygen  pressure  of  the  arterial  blood  and  contrasting  it  with  that 
of  the  alveolar  or  of  the  inspired  air  were  then  at  our  disposal. 

Our  first  experiments  on  man  were  taken  up  with  determining 
the  arterial  oxygen  pressure  under  as  normal  conditions  as  pos- 
sible, and  we  especially  wished  to  guard  against  the  effects  of 
deficiency  of  oxygen.  We  therefore  employed  a  low  saturation 
(23  per  cent)  of  the  blood  with  CO  and  made  sure  that  the  res- 
piration apparatus  contained  a  normal  atmosphere  by  ventilating 
it  freely  with  fresh  air  before  the  experiment.  All  the  experiments 
were  made  with  the  subject  sitting  at  rest. 


234  RESPIRATION 

The  results  of  these  experiments  are  collected  in  the  accom- 
panying table. 

The  figures  show  quite  distinctly  that  under  normal  circum- 
stances when  the  subject  is  at  rest  the  arterial  oxygen  pressure  in 
man  corresponds  exceedingly  closely  to  the  pressure  of  oxygen  in 
the  alveolar  air.  In  fact  in  no  single  instance  does  the  value  of  the 
arterial  oxygen  pressure  differ  from  the  alveolar  by  a  greater 
amount  than  can  be  accounted  for  by  the  experimental  error  of 
the  method. 

We  then  tested  the  effect  of  raising  the  alveolar  oxygen  pressure 
considerably  above  the  normal  value  by  filling  the  respiration 
apparatus  with  an  atmosphere  rich  in  oxygen.  The  results  of  the 
experiments  are  also  given  in  the  table.  Here  again  the  figures 
show  that  the  arterial  and  alveolar  oxygen  pressures  have  prac- 
tically identical  values.  In  these  experiments  on  man  we  were 
content  to  use  only  a  moderate  increase  of  the  alveolar  oxy- 
gen pressure,  for  the  higher  the  oxygen  pressure  is  raised  the 
less  proportional  difference  is  there  between  the  inspired  air  and 
the  alveolar  air.  A  point  will  therefore  eventually  be  reached 
when  the  determination  of  the  difference  of  tint  between  the  blood 
withdrawn  from  the  body  and  that  saturated  with  the  inspired 
air  in  vitro  will  fall  almost  within  the  experimental  errors  of  the 
method.  It  should  be  noted  that  in  these  experiments  the  car- 
bonic acid  in  the  alveolar  air  had  precisely  its  normal  value, 
namely  5.6  per  cent  when  measured  dry,  and  we  have  therefore 
no  reason  to  suppose  that  the  alveolar  air  samples  were  other 
than  normal. 

Having  obtained  thus  results  which  indicated  that  during  rest 
under  normal  conditions  the  transference  of  oxygen  through  the 
pulmonary  epithelium  occurs  without  active  secretory  interven- 
tion of  the  alveolar  epithelium,  we  were  naturally  anxious  to  test 
the  matter  further  under  conditions  in  which  some  amount  of 
deficiency  of  oxygen  might  affect  the  subject.  The  necessary  de- 
ficiency of  oxygen  was  obtained  by  exposing  the  subject  to  an 
atmosphere  containing  a  considerably  lower  percentage  of  oxy- 
gen than  the  normal.  The  experimental  procedure  was  precisely 
the  same  as  before,  save  that  we  filled  the  respiration  apparatus 
before  the  start  with  an  appropriate  atmosphere  by  the  method 
described  above.  The  results  of  these  experiments  are  collected 
in  the  middle  part  of  the  table. 

The  partial  pressure  of  oxygen  in  the  air  breathed  corresponded 


RESPIRATION  235 

to  an  altitude  of  15,000  feet  or  over;  yet  we  noted  that  a  23  per 
cent  saturation  of  the  blood  with  carbon  monoxide  was  tolerated 
without  inconvenience.  One  of  the  subjects  was  liable  to  head- 
ache when  his  blood  was  saturated  to  25  per  cent  or  more  with 
carbon  monoxide,  but  this  was  in  no  wise  accentuated  in  these 
experiments.  That  deficiency  of  oxygen  was  exerting  its  custom- 
ary effect  on  the  respiration  is  indicated  by  the  low  value  of  the 
alveolar  carbonic  acid  percentage.  Both  the  subjects  noticed  dis- 
tinct hyperpnoea  for  some  time  after  commencing  to  breathe  into 
the  respiration  apparatus,  and  that  this  was  accentuated  on  the 
slightest  movement.  The  face  remained  of  a  distinctly  bluish 
color  throughout  the  experiment,  but  the  blueness  passed  away 
if  the  hyperpnoea  became  exaggerated  for  a  short  time  by  mus- 
cular movement.  On  rebreathing  normal  air  at  the  close  of  the 
experiment  well-marked  Cheyne-Stokes  breathing  was  once  or 
twice  observed,  indicating  that  the  want  of  oxygen  had  induced  a 
real  hyperpnoea  which  had  lowered  the  general  carbonic  acid 
pressure  in  the  body  considerably. 

In  calculating  the  arterial  oxygen  pressures  from  the  experi- 
mental data  of  these  experiments,  it  was  necessary  to  make  allow- 
ance for  the  fact  that  the  arterial  blood  was  not  fully  saturated 
with  oxygen  and  CO,  while  the  blood  from  the  saturator  must  have 
been  almost  completely  saturated,  as  the  oxygen  pressure  in  the 
air  of  the  saturator  was  considerably  higher,  and  hardly  any  CO2 
was  present.  For  the  correction  required  under  these  circum- 
stances I  must  refer  to  our  original  paper. 

On  looking  at  the  results  of  the  four  experiments  it  will  be  seen 
that  in  every  case  the  arterial  was  above  the  alveolar  oxygen  pres- 
sure. The  mean  difference  seems  to  be  outside  the  limits  of  experi- 
mental error,  but  only  amounts  to  8  mm. 

A  further  series  of  experiments  was  made  with  the  subject 
doing  muscular  work.  Preliminary  experiments  made  with  the 
work  done  on  a  tricycle  ergometer  had  shown  that  when  the 
breathing  was  greatly  increased  difficulties  arose  with  the  appa- 
ratus. We  therefore  decided  to  make  use  of  work  with  only  one 
arm.  This  enabled  us  to  push  the  work  to  the  point  of  fatigue, 
when  want  of  oxygen  would  be  produced  in  the  muscles,  with 
formation  of  lactic  acid.  That  lactic  acid  was  actually  formed  is 
indicated  by  the  low  alveolar  CO2  percentages.  The  work  appa- 
ratus which  we  employed  was  of  the  simplest  description.  It 
consisted  of  a  lever  which  could  be  moved  backwards  and  for- 
wards, and  transmitted  its  motion  by  means  of  a  connecting  rod  to 


236  RESPIRATION 

a  small  table  carrying  a  weight  which  slid  to  and  fro  upon  a 
smooth  plank,  to  one  end  of  which  the  lever  was  pivoted. 

The  work  apparatus  was  placed  upon  the  ground  adjacent  to 
the  chair  on  which  the  subject  sat,  so  that  he  could  move  the  lever 
and  yet  breathe  comfortably  into  the  respiratory  apparatus.  By 
increasing  the  weight  the  amount  of  work  done  by  the  subject 
could  be  raised.  It  was  not  possible  to  measure  the  actual  work 
done  in  mechanical  units,  but  we  could  do  so  in  physiological 
units  by  observing,  by  means  of  the  small  gas  meter,  the  effect 
on  the  oxygen  consumption  of  the  subject  per  minute.  What  we 
term  "moderate  work"  in  the  tables  below  was  sufficient  to  raise 
the  total  oxygen  consumption  to  one  and  a  half  times  its  resting 
value,  while  "severe  work"  doubled  the  resting  oxygen  consump- 
tion. Work  which  doubles  the  resting  oxygen  consumption  is  only 
equivalent  to  walking  on  the  flat  at  two  miles  per  hour,  and  does 
not  sound  particularly  severe,  but  we  found  it  sufficiently  tiring 
when  it  was  performed  by  one  arm  only,  and  kept  up  for  half  an 
hour  at  a  time. 

The  lower  part  of  Table  III  shows  the  results  of  the  work  ex- 
periments. These  results  are  very  striking :  for  the  arterial  oxygen 
pressure  was  on  an  average  4.4  per  cent,  or  32  mm.  of  mercury, 
above  the  alveolar  oxygen  pressure,  and  in  two  experiments  was 
8.5  and  15.6  mm.  above  the  oxygen  pressure  of  the  inspired  air 
(allowing  for  aqueous  vapor). 

In  the  last  experiment  on  the  table  the  effects  of  muscular  work 
and  low  oxygen  in  the  inspired  air  were  combined.  It  will  be  seen 
that  the  arterial  was  33.5  mm.  above  the  alveolar  oxygen  pressure, 
whereas  with  a  low  oxygen  in  the  inspired  air  and  no  work  the 
arterial  never  exceeded  the  alveolar  oxygen  pressure  by  more  than 
13  mm.  As  already  mentioned,  it  was  noticed  that  when  work 
was  done  while  a  low  oxygen  percentage  was  being  breathed  the 
lips  and  face  lost  the  bluish  color  due  to  the  low  oxygen,  and 
became  of  a  normal  red  color.  It  was  also  noticed  many  years  ago 
by  Loewy25  that  even  a  slight  muscular  exertion  produced  a 
marked  improvement  in  the  subjective  symptoms  of  want  of  oxy- 
gen in  a  steel  chamber  at  low  atmospheric  pressure.  Our  results 
on  the  arterial  oxygen  pressure  during  muscular  exertion  furnish 
an  evident  clue  to  these  observations. 

"Loewy.  Untersuchungen  u.  d.  Respiration  und  Circulation,  Berlin,  1895, 
p.  1 6.  The  fact  that  Geppert  and  Zuntz  (PfLiiger's  Archiv,  XLII,  p.  189,  1888) 
found  a  little  more  oxygen  in  arterial  blood  during  work  than  during  rest  may 
point  also  in  the  same  direction. 


RESPIRATION  237 

In  a  former  chapter  I  have  referred  to  some  of  the  results  of 
the  expedition  to  Pike's  Peak  undertaken  in  1911  by  Professors 
Yandell  Henderson  and  Schneider,  Dr.  Douglas,  and  myself.26 
Part  of  our  object  was  to  determine  whether  the  want  of  oxygen 
due  to  the  rarefied  air  at  14,000  feet  did  not  produce  active  secre- 
tion of  oxygen  inwards.  We  used  the  same  method  as  at  Oxford, 
taking  every  precaution  against  errors.  The  results  were  quite 
unmistakable.  We  found  that  as  soon  as  acclimatization  to  the  air 
was  established  the  arterial  oxygen  pressure  became  considerably 
higher  than  that  of  the  alveolar  air.  The  next  table  shows  our 
results.  In  ordinary  resting  experiments  on  acclimatized  persons, 
the  arterial  oxygen  pressure  was  on  an  average  about  70  per  cent 
above  the  alveolar  oxygen  pressure.  When,  however,  air  extra 
rich  in  oxygen  was  breathed,  so  that  the  alveolar  oxygen  pressure 
rose  to  about  what  it  is  at  sea  level,  the  difference  between  arterial 
and  alveolar  oxygen  pressure  fell  to  8  or  I o  per  cent,  even  during 
the  short  period  of  an  experiment.  In  a  subject  investigated  im- 
mediately on  arrival  at  the  summit  by  the  cogwheel  railway  the 
arterial  was  only  about  15  per  cent  above  the  alveolar  oxygen 
pressure,  whereas  three  days  later,  after  acclimatization,  the  ex- 
cess was  100  per  cent. 

The  Pike's  Peak  results  threw  much  new  light  on  oxygen  secre- 
tion by  the  lungs,  and  on  the  former  experiments  at  Oxford.  It 
was  evident,  that  not  only  is  oxygen  want  a  stimulus  to  active 
oxygen  secretion  by  the  lungs,  but  that  the  response  to  the  stimulus 
improves  greatly  with  practice  or  "acclimatization,"  just  as  is 
the  case  with  other  physiological  responses.  We  can  now  see  why 
some  experiments — for  instance  those  which  Lorrain  Smith  and  I 
made  jointly  on  ourselves,  indicated  oxygen  secretion,  while  other 
experiments  in  which  the  physical  and  chemical  conditions  seemed 
to  be  the  same  gave  negative  results.  It  was  the  physiological  con- 
ditions which  were  different.  In  the  latter  experiments  we  were 
not  acclimatized  against  anoxaemia. 

It  is  easy  to  see  the  physiological  advantage  of  oxygen  secretion 
as  a  defense  against  the  anoxaemia  of  high  altitudes  and  similar 
conditions,  or  against  carbon  monoxide  poisoning;  but  its  uses 
under  ordinary  conditions,  where  nothing  but  pure  air  at  about 
ordinary  atmospheric  pressure  is  breathed,  are  not  so  obvious.  It 
is  clear  that  as  the  arterial  haemoglobin  is  nearly  saturated  with 
oxygen,  during  rest,  at  any  rate,  without  any  active  secretion, 

29  Douglas,  Haldane,  Yandell  Henderson,  and  Schneider,  Phil.  Trans.  Roy.  Soc., 
(B)  299,  p.  195,  1913. 


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RESPIRATION  239 

hardly  anything  could  be  gained  by  secretion,  since  any  additional 
oxygen  which  could  be  added  to  the  blood  would  be  trifling  in 
amount  unless  with  an  enormous  secretory  pressure  such  as  has 
never  been  found  experimentally.  We  can  thus  readily  under- 
stand why  there  is  no  secretion  during  rest  under  normal  condi- 
tions, as  our  experiments  clearly  showed  to  be  the  case.  It  was 
only  during  work  that  the  experimental  results  showed  secretion ; 
but  as  a  matter  of  fact  the  increase  found  in  the  arterial  oxygen 
pressure  above  the  alveolar  oxygen  pressure  would  be  of  very 
little  service  in  charging  the  blood  further  with  oxygen ;  and  this 
brings  us  back  to  the  original  question. 

In  the  first  place  it  must  be  pointed  out  that  the  experiments 
which  Douglas  and  I  made  on  oxygen  secretion  during  muscular 
work  were  carefully  arranged  in  such  a  way  as  to  demonstrate  the 
existence  of  secretion  if  any  secretion  occurred  during  muscular 
work.  We  knew  already  that  the  stimulus  to  oxygen  secretion 
came  from  anoxaemia  of  the  tissues.  We  knew,  also,  that  the 
only  probable  function  of  oxygen  secretion  was,  not  to  raise  the 
arterial  oxygen  above  that  of  the  alveolar  air,  but  to  prevent  a 
serious  fall,  such  as  otherwise  might  take  place  during  work  suffi- 
cient to  increase  very  greatly  the  oxygen  requirements  of  the 
body.  But  we  had  no  index  of  what  the  fall  might  be  in  the  absence 
of  secretion.  We  therefore  made  the  experiments  in  such  a  way 
that  tiring  work,  such  as  would  presumably  furnish  the  stimulant 
to  oxygen  secretion,  was  done  with  one  arm  only.  The  oxygen 
requirements  of  the  body  were  in  this  way  only  increased  to  a 
very  moderate  extent,  so  that  oxygen  secretion  would  have  every 
chance  to  raise  the  arterial  oxygen  pressure  above  the  alveolar 
oxygen  pressure,  just  as  in  CO  poisoning  or  at  high  altitudes  dur- 
ing rest.  It  was  also  much  easier  to  make  the  experiments  accu- 
rately when  the  oxygen  intake  was  not  greatly  increased. 

Since  our  original  experiments,  and  those  on  Pike's  Peak,  were 
carried  out,  a  good  deal  of  both  direct  and  indirect  evidence  has 
accumulated  in  confirmation  of  our  conclusions,  and  must  now  be 
referred  to.  In  Chapter  VII  the  very  clear  physiological  evidence 
was  summarized,  showing  that  there  is,  in  persons  who  are  not  in 
good  physical  training,  considerable  anoxaemia  during  hard  mus- 
cular exertion.  This  is  not  merely  local  anoxaemia  in  the  muscles 
with  the  associated  formation  of  lactic  acid  described  in  Chapter 
VIII :  for  if  the  work  is  not  too  hard  the  respiratory  symptoms 
indicating  anoxaemia  are  still  present  during  the  work,  but  there 
is  no  trace  of  a  subsequent  fall  in  the  resting  alveolar  CO2  pres- 


240  RESPIRATION 

sure.  This  fall  is  the  physiological  indication  of  lactic  acid,  and 
runs  parallel,  as  already  mentioned,  with  the  presence  of  much 
lactic  acid  in  the  blood  and  urine.  As  Douglas  and  his  pupils  have 
found,27  there  is,  as  a  matter  of  fact,  practically  no  increase  in 
the  lactic  acid  present  in  the  urine  during  moderate  work.  Thus  the 
anoxaemia  cannot  well  t>€  due  to  anything  else  but  imperfect 
saturation  of  the  arterial  blood  with  oxygen ;  and  that  this  is  the 
actual  cause  is  directly  shown  by  the  fact  that  a  very  moderate 
increase  in  the  oxygen  percentage  of  the  air  breathed  relieves  the 
symptoms. 

In  ordinary  persons  not  in  good  physical  training  a  very  mod- 
erate diminution  in  atmospheric  pressure  is  quite  sufficient  to 
cause  a  noticeable  excess  of  hyperpnoea  on  any  considerable  ex- 
ertion, such  as  climbing  or  walking  fast.  This  is  very  evident  on 
going  by  train  to  some  place  four  or  five  thousand  feet  above  sea 
level;  and  the  cause  is,  without  a  shadow  of  doubt,  imperfect 
oxygenation  of  the  arterial  blood.  At  ordinary  atmospheric  pres- 
sure we  are  accustomed  to  a  certain  degree  of  hyperpnoea  and 
exhaustion  with  a  given  degree  of  muscular  exertion.  That  this 
is  in  part  dependent  on  imperfect  saturation  of  the  arterial  blood 
is  only  revealed  by  the  fact  that  in  air  at  a  higher  atmospheric 
pressure  (as  in  the  case  of  workers  in  compressed  air,  and  prob- 
ably in  deep  mines),  or  when  air  enriched  with  oxygen  is 
breathed,  the  same  work  becomes  much  easier,  at  any  rate  to  many 
persons. 

The  observations  of  Dr.  Henry  Briggs,  described  in  Chapter 
VII,  show  that  there  is  a  striking  difference  in  this  respect  be- 
tween men  in  good  physical  training  and  ordinary  persons,  as  the 
former  class  get  no  benefit  from  air  enriched  with  oxygen  unless 
the  work  is  excessively  hard,  while  the  latter  get  great  benefit, 
shown,  not  only  by  the  much  greater  ease  and  comfort  with  which 
they  perform  the  work,  but  by  the  smaller  amount  of  air  which 
they  require  to  breathe.  The  corresponding  difference  at  high 
altitudes  is  perfectly  familiar  to  mountaineers.  The  man  who  is  in 
good  training  is  free  from  the  hyperpnoea,  mountain  sickness,  and 
other  effects  of  high  altitudes  to  a  far  greater  extent  than  the  man 
who  is  not  in  training;  and  this  evident  fact  has  often  led 
mountaineers  to  the  mistaken  conclusion  that  mountain  sickness 
has  nothing  to  do  with  altitude  or  anoxaemia,  but  is  simply  a  sign 
of  imperfect  training. 

"Campbell,  Douglas,  and  Hobson,  Phil.  Trans.  Roy.  Soc.,  (B),  Vol.  210,  p.  x, 
1920. 


RESPIRATION  241 

All  the  facts  just  mentioned  confirm  the  direct  evidence  in 
favor  of  oxygen  secretion  in  the  lungs.  Part  of  the  exhaustion  of 
hard  physical  work  is  due  to  imperfect  saturation  of  the  arterial 
blood  with  oxygen  and  the  consequent  effects  on  the  respiratory 
center  and  central  nervous  system  as  already  described  in  Chap- 
ters VI  and  VII.  In  persons  who  are  in  good  physical  training 
these  effects  are  in  abeyance  because  as  one  part  of  physical  train- 
ing the  lung  epithelium  has  become  much  more  capable  of  re- 
sponding to  the  stimulus  calling  forth  increased  secretion  of 
oxygen,  just  as  in  the  case  of  a  man  who  has  become  acclimatized 
to  a  high  altitude,  or  to  breathing  air  containing  a  small  per- 
centage of  CO.  It  is  the  training  of  the  lung  epithelium,  and  not 
anything  else,  that  makes  the  specific  difference.  This  is  shown 
at  once  by  the  fact  that  acclimatization  to  high  altitudes  or  CO 
poisoning  takes  place  whether  a  man  takes  exercise  or  not. 

In  this  connection  I  may  mention  the  result  of  an  experiment 
which  I  made  for  a  specific  object  during  the  war.  It  seemed 
desirable  to  find  out  how  soon  the  fall  in  oxygen  percentage  in  the 
air  of  a  submarine  would  begin  to  have  serious  effects.  I  there- 
fore shut  myself  in  an  air-tight  respiration  chamber  which  was 
provided  with  the  same  sort  of  purifier  for  absorbing  the  CO2 
produced  by  respiration  as  was  used  in  British  submarines.  The 
oxygen  percentage  was  also  allowed  to  fall  at  the  same  slow  rate 
as  that  at  which  it  had  been  found  to  fall  in  the  most  crowded 
submarines  then  in  use.  After  a  few  hours  a  light  would  no  longer 
burn  in  the  air,  and  in  a  few  more  hours  even  a  lighted  pipe 
handed  in  through  a  small  air  lock  would  no  longer  keep  alight. 
After  56  hours  the  oxygen  percentage  had  fallen  below  10.  I  then 
terminated  the  experiment  as  the  purifier  was  failing,  and  the 
immediate  object  of  the  experiment,  which  was  to  find  out  whether 
the  air  in  a  submarine  would  last  easily  for  48  hours  without  any 
addition  of  oxygen,  had  been  attained.  I  had  no  trace  of  mountain 
sickness  or  any  other  symptom  of  anoxaemia,  and  my  lips  were 
just  as  red  as  usual,  though  from  other  experiments  described 
in  Chapter  VII,  I  knew  that  without  acclimatization  I  should  have 
broken  down  hopelessly  in  the  existing  atmosphere.  A  laboratory 
attendant  who  afterwards  went  into  the  chamber  along  with  me 
became  blue  and  uncomfortable,  and  finally  collapsed  and  had  to 
be  pulled  out  hurriedly. 

In  this  experiment  the  fall  in  oxygen  percentage  had  been  so 
slow  that  acclimatization  had  kept  pace  in  me  with  the  fall  in 
oxygen  percentage,  just  as  when  a  man  ascends  only  very  gradu- 


242  RESPIRATION 

ally  to  a  high  altitude.  There  is,  however,  much  more  in  this 
acclimatization  than  mere  increase  in  the  power  of  oxygen  secre- 
tion, since  there  is  also  the  gradual  adjustment  of  blood  reaction 
to  increased  breathing,  as  explained  fully  in  Chapter  VIII. 

In  a  more  recent  series  of  experiments  by  Kellas,  Kennaway, 
and  myself28  these  two  effects  were  separated.  One  of  our  objects 
was  to  see  how  far  acclimatization  to  high  altitudes  could  be  ob- 
tained by  discontinuous  exposures  to  low  barometric  pressures. 
This  question  is  of  course  of  considerable  importance  to  airmen, 
in  whom  the  exposures  are  discontinuous.  The  effects  produced 
before  acclimatization  on  Dr.  Kellas,  myself,  and  others,  by  an 
exposure  to  320  or  330  mm.  barometric  pressure,  are  described 
in  Chapter  VI.  To  obtain  acclimatization  we  used  the  method  of 
exposing  ourselves  for  six  to  eight  hours  to  atmospheric  pressures 
of  500,  430,  and  360  mm.  on  three  successive  days.  We  found,  how- 
ever, that  our  resting  alveolar  CO2  pressure  had  always  returned 
to  normal  before  the  morning  after  each  successive  exposure. 
Thus  there  was  no  lasting  adjustment  of  blood  reaction  to  in- 
creased breathing,  as  any  change  in  this  direction  had  disappeared 
by  the  morning.  There  was  also  no  lasting  increase  in  our  haemo- 
globin percentages.  Any  acclimatization  obtained  must  therefore, 
apparently,  be  due  to  increased  power  of  oxygen  secretion. 

The  result  of  the  experiment  was  that  there  was  marked  ac- 
climatization, but  limited  in  amount.  When  unacclimatized  I  had 
been  totally  disabled,  and  had  lost  all  memory,  at  a  pressure  of 
320  mm.,  as  already  described.  But  on  the  last  day  of  the  ac- 
climatization we  stayed  at  315  mm.  for  a  considerable  time,  during 
which,  though  we  were  distinctly  blue,  I  could  quite  easily  con- 
tinue to  do  gas  analyses  and  other  operations,  and  move  about 
as  usual,  with  no  loss  of  memory  afterwards  of  what  had  occurred. 
In  this  experiment  my  son,  Captain  J.  B.  S.  Haldane,  acted  as  an 
unacclimatized  control.  He  came  in  with  us  and  stayed  for  some 
time  at  366  mm. ;  but  after  two  hours  he  was  so  much  affected  that 
we  had  to  let  him  out.  His  breathing  had  become  increasingly 
rapid  and  shallow,  and  he  had  gradually  sunk  into  a  stupefied 
condition.  After  coming  out  he  could  remember  hardly  anything 
of  the  last  hour  in  the  chamber. 

It  is  clear  from  this  experiment  that  airmen,  so  long  as  they 
retain  their  health,  and  remain  at  high  altitudes  pretty  fre- 
quently, must  be  capable  of  acquiring  a  considerable  degree  of 

28  Haldane,  Kellas,  and  Kennaway,  Journ.  of  Physiol.,  LIII,  p.  181,  1919- 


RESPIRATION  243 

acclimatization.  This  acclimatization  was  long  ago  noted  by 
Glaisher  in  connection  with  his  occasional  high  balloon  ascents. 
An  equal  degree  of  acclimatization  can  undoubtedly  be  main- 
tained in  a  simpler  manner  by  good  physical  training;  and  at 
heights  of  less  than  about  20,000  feet  an  airman  in  good  physical 
training  should  have  little  difficulty  from  anoxaemia.  It  must  be 
noted,  however,  that  even  a  small  degree  of  the  neurasthenia  with 
shallow  breathing  described  in  Chapter  III  renders  an  airman 
totally  incapable  of  going  to  any  considerable  height  without  an 
oxygen  apparatus. 

Our  acclimatization  experiment  indicated  that  with  complete 
acclimatization,  including  adjustment  of  the  blood  reaction  to 
the  increased  breathing,  and  increase  in  the  haemoglobin  per- 
centage, a  man  could  probably,  if  the  mere  physical  difficulties 
were  not  too  great,  reach  the  summit  of  Mount  Everest  without 
breathing  anything  else  than  ordinary  air,  though  he  would 
quite  certainly  die  at  this  altitude  if  he  were  not  acclimatized. 

It  was  pointed  out  in  Chapters  III  and  VII  that,  on  account  of 
the  imperfect  distribution  of  air  in  the  lungs,  the  average  alveolar 
oxygen  pressure  is,  even  during  rest  under  normal  healthy  condi- 
tions, no  certain  guide  to  the  oxygen  pressure  of  the  mixed 
arterial  blood.  During  heavy  work  this  must  be  so  to  an  increased 
degree,  since,  although  the  expansion  of  the  lungs  is  much  better, 
the  rate  at  which  oxygen  is  absorbed  is  enormously  greater. 
Meakins  and  Davies29  have  recently  made  exact  determinations 
of  the  percentage  saturation  with  oxygen  of  the  haemoglobin  in 
the  arterial  blood  of  a  number  of  healthy  persons,  and  found  it  to 
vary  from  94  to  96  per  cent  in  different  persons,  the  variation 
depending  probably  on  the  differences  in  the  oxyhaemoglobin 
curves  which  Barcroft  discovered  (Chapter  IV).  In  my  own  case 
the  saturation  was  94.3  per  cent.  This  is  not  much  lower  than  96 
per  cent,  the  saturation  which  would  be  expected  if  my  arterial 
blood  were  fully  saturated  to  the  oxygen  pressure  of  the  mixed 
alveolar  air.  If,  however,  we  look  at  the  dissociation  curve  of 
the  oxyhaemoglobin  of  human  blood,  we  see  that  94.3  per  cent 
saturation  corresponds  to  an  oxygen  pressure  of  only  11.2  per 
cent  of  an  atmosphere,  as  compared  with  13.2  per  cent  in  the 
alveolar  air.  Thus  the  oxygen  pressure  in  the  mixed  arterial  blood 
is  very  distinctly  less  than  in  the  alveolar  air ;  and  this  is  the  sort 
of  result  which  the  aerotonometer  gives,  as  already  explained. 

"Meakins  and  Davies,  Journ.  of  Pathol.  and,  Bacter.,  XXIII,  p.  453,  1920. 


244  RESPIRATION 

On  the  other  hand  the  carbon  monoxide  method  gives,  during 
rest  under  normal  conditions,  exactly  the  same  oxygen  pressure 
in  the  arterial  blood  as  in  the  alveolar  air.  This  difference  in  the 
results  by  the  two  methods  used  to  be  rather  a  puzzle,  and  was 
explained  by  me  as  probably  due,  either  to  a  process  of  rapid  but 
slight  oxidation  in  the  blood  itself,  or  to  a  little  blood  getting 
through  the  lungs  without  exposure  to  alveolar  air.  Our  shallow 
breathing  experiments,  and  the  neurasthenia  cases,  showed 
clearly  enough  why  the  mixed  arterial  blood  is  not  fully  saturated 
to  the  alveolar  pressure;  but  why  does  the  carbon  monoxide 
method  not  show  this?  A  little  consideration  will  show  the  reason. 
The  carbon  monoxide  method  gives  the  average  arterial  oxygen 
pressure  of  all  the  portions  of  arterial  blood  leaving  the  lung 
alveoli,  just  as  the  "alveolar  air"  gives  the  average  oxygen  pres- 
sure of  all  the  portions  of  air  in  the  alveoli  of  the  air-sac  system. 
But  the  oxygen  pressure  of  the  mixed  arterial  blood  cannot  be 
deduced,  as  fully  explained  in  Chapter  IV,  from  the  average  of 
the  oxygen  pressures  in  the  blood  leaving  the  alveoli.  It  is  this 
average  that  the  carbon  monoxide  method  gives.  Hence  for  the 
purpose  of  deducing  the  oxygen  pressure  of  the  mixed  arterial 
blood  the  carbon  monoxide  method  has  exactly  the  same  defects 
as  the  method  of  inferring  this  value  from  the  oxygen  pressure  of 
the  alveolar  air  on  the  assumption  (perfectly  valid  for  resting 
conditions  at  ordinary  atmospheric  pressure  when  pure  air  is 
breathed)  that  diffusion  equilibrium  is  established  between  al- 
veolar air  and  blood.  For  the  purpose,  however,  of  deciding 
whether  or  not  active  secretion  of  oxygen  is  occurring,  the  carbon 
monoxide  method  is  perfectly  valid.  It  gives  just  the  information 
needed;  and  for  this  purpose  it  is  far  more  reliable  than  the 
aerotonometer  method,  which  has  always  given  misleading  in- 
formation on  the  question  of  diffusion  equilibrium  for  oxygen, 
and  made  it  appear  as  if  diffusion  equilibrium  is  never  attained, 
even  during  complete  rest. 

To  those  who  pin  their  faith,  as  regards  the  secretion  question, 
to  the  aerotonometer  results,  I  may  perhaps  point  out  that  if  they 
were  accepted  as  evidence  they  would  completely  wreck  the  dif- 
fusion theory.  For  if  diffusion  equilibrium  is  not  even  obtained 
under  resting  conditions  under  normal  barometric  pressure  it 
would  be  quite  inconceivable  on  the  diffusion  theory  that  anything 
approaching  to  diffusion  equilibrium  would  be  obtained  during 
muscular  work,  and  particularly  at  high  altitudes.  Yet  on  Pike's 


RESPIRATION  245 

Peak  is  was  possible  to  do  hard  muscular  work  with  .the  lips  re- 
maining quite  red. 

It  will  easily  be  seen  on  consideration  that  as  the  barometric 
pressure,  or  the  oxygen  percentage  of  the  inspired  air,  is  pro- 
gressively reduced,  the  difference  in  percentage  saturation  be- 
tween the  mixed  arterial  blood  and  blood  completely  saturated  at 
the  existing  alveolar  oxygen  pressure  will  increase  more  and  more 
if  diffusion  alone  determines  the  saturation  of  the  blood  in  the 
lungs,  and  will  tend  in  the  same  direction  even  if  active  secretion 
assists  diffusion.  We  can  thus  easily  explain  why  some  of  the 
persons  who  ascended  Pike's  Peak  were  very  blue  in  the  face,  and 
why  fainting  or  partial  loss  of  consciousness  were  common  occur- 
rences. We  can  also  understand  why  some  persons  become  more 
or  less  unwell  at  first  on  going  to  an  altitude  of  only  four  or  five 
thousand  feet,  and  why  in  all  persons  there  is  a  distinct  physio- 
logical reaction  to  anoxaemia,  as  shown  by  lowering  of  the  al- 
veolar CO2  pressure  and  rise  in  the  haemoglobin  percentage.  This 
physiological  reaction  would  be  difficult  to  understand  if  there 
was  uniform  saturation  of  the  haemoglobin  in  all  the  alveoli.  We 
must  conclude  that  whether  or  not  a  person  is  acclimatized  to  a 
low  barometric  pressure  the  percentage  saturation  of  the  mixed 
arterial  haemoglobin  with  oxygen  is  distinctly  diminished,  though 
the  amount  of  the  diminution  is  not  indicated  by  the  carbon  mon- 
oxide method. 

In  the  process  of  oxygenation  of  the  blood  in  the  lungs,  the 
oxygen  has  to  pass  from  the  alveolar  air  through  a  thin  layer  of 
living  tissue  into  the  blood  and  into  the  corpuscles.  This  process 
must  take  some  time.  To  the  genius  of  Christian  Bohr  we  owe  the 
principle  of  a  method  by  which  the  time  may  be  estimated,  in  so 
far  as  the  process  is  one  of  diffusion.  In  connection  with  the  ab- 
sorption of  oxygen  by  the  lungs  it  is  not  possible  to  measure  the 
rate  at  which,  with  a  given  diffusion  pressure,  oxygen  passes 
inwards,  because  we  do  not  know  the  mean  diffusion  pressure. 
We  can,  as  will  be  shown  later,  measure  the  oxygen  pressure  of 
the  venous  blood,  as  well  as  that  of  the  alveolar  air  and  arterial 
blood ;  but  we  do  not  know  how  quickly  the  blood  becomes  satu- 
rated in  its  passage  along  the  alveolar  capillaries.  Hence  we  can- 
not estimate  the  mean  difference  in  oxygen  pressure  required  for 
the  diffusion  inwards  of  a  given  quantity  of  oxygen  in  a  given 
time.  In  the  case  of  absorption  of  CO  present  in  the  air  in  a  low 
proportion  the  conditions  are  quite  different,  however:  for  we 
can  determine  the  percentage  of  CO  in  the  alveolar  air,  and  the 


246  RESPIRATION 

rate  at  which  the  gas  is  absorbed,  while,  for  short  experiments, 
the  difference  in  CO  pressure  between  the  alveolar  air  and  the 
blood  is  constant.  In  this  way  we  can  tell  how  much  CO  is  ab- 
sorbed per  minute  with  a  given  pressure  difference;  and  from 
this,  allowing  for  the  greater  solubility  and  slightly  lower  dif- 
fusibility  of  oxygen,  we  can  calculate  the  rate  at  which  oxygen 
diffuses  in  with  the  same  pressure  difference. 

Bohr's  original  calculations  (based  on  rather  rough  experi- 
ments made  by  myself  for  another  purpose)  were  not  very  ac- 
curate ;  but  the  matter  was  reinvestigated  by  A.  and  M.  Krogh,30 
and  still  more  recently  by  M.  Krogh.31  A.  and  M.  Krogh  found 
that  for  adults  about  25  cc.  of  oxygen  will  diffuse  inwards  per 
minute  for  every  I  mm.  of  difference  in  oxygen  pressure  during 
rest,  and  about  35  cc.  during  work.  The  estimate  of  M.  Krogh  is 
considerably  higher ;  but  I  do  not  think  that  the  method  which  she 
used  was  at  all  reliable,  for  the  following  reasons.  The  method 
consisted  in  taking  in  a  deep  breath  of  air  containing  a  small 
percentage  of  CO.  Part  of  this  breath  was  then  breathed  out,  and 
a  sample  of  the  alveolar  air  taken.  The  rest  of  the  breath  was 
held  for  a  measured  interval  of  time,  after  which  a  second  sample 
of  alveolar  air  was  taken,  and  the  percentages  of  CO  in  the  two 
samples  very  accurately  determined.  From  the  fall  in  the  per- 
centage of  CO  between  the  two  samples  the  rate  of  absorption  of 
the  CO  was  then  calculated. 

If  the  difference  between  the  percentages  of  CO  in  the  two 
samples  represented  absorption  of  CO,  the  method  would  be  a 
correct  one.  Actually,  however,  it  is  quite  impossible,  as  I  have 
convinced  myself  by  repeated  experiments  with  various  gas  mix- 
tures, to  secure  an  even  distribution  of  a  gas  through  the  lung  air 
by  taking  in  a  single  deep  breath.  The  first  alveolar  sample  con- 
tains an  undue  proportion  of  the  atrial  air  containing  a  higher 
initial  percentage  of  CO,  while  the  second  sample  comes  ex- 
clusively from  the  alveoli  of  the  air-sac  system,  in  which  the  per- 
centage of  CO  was  never  nearly  so  high  as  in  the  atria.  Thus  the 
apparent  absorption  of  CO  during  the  interval  of  holding  the 
breath  is  much  greater  than  the  actual  absorption.  The  method  is 
thus  fallacious;  and  the  same  criticism  applies  to  a  number  of 
other  Copenhagen  experiments  with  regard  to  alveolar  air,  the 
dead  space  in  breathing,  etc. 

Taking,  however,  the  earlier  estimate  of  A.  and  M.  Krogh,  it 

30  A.  and  M.  Krogh,  Skand.  Arch.  f.  Physiol.,  XXIII,  p.  236,  1910. 

31  M.  Krogh,  Journ.  of  Physwl.,  XLIX,  p.  271,  1915. 


RESPIRATION  247 

can  be  calculated32  that  during  rest  at  normal  atmospheric  pres- 
sure, the  arterial  blood  passing  through  an  average  alveolus 
would  easily  be  saturated  by  simple  diffusion  to  the  oxygen  pres- 
sure of  the  air  in  the  alveolus.  During  considerable  muscular  work, 
however,  this  would  not  be  the  case ;  and  the  arterial  blood  would 
emerge  incompletely  saturated.  That  there  should  be  some  an- 
oxaemia during  considerable  exertion  is  therefore  exactly  what 
might  be  anticipated  on  the  diffusion  theory,  even  without  any 
allowance  for  the  effects  of  uneven  distribution  of  air  and  blood 
among  different  alveoli.  When  allowance  is  also  made  for  this 
factor,  the  presence  of  anoxaemia  during  even  very  moderate 
exertion  at  ordinary  atmospheric  pressure  in  persons  not  physi- 
cally fit  is  just  what  might  be  expected;  and  at  high  altitudes  the 
anoxaemia  would  be  so  serious  as  to  make  any  considerable  ex- 
ertion impossible  but  for  active  secretion. 

All  the  facts,  therefore,  and  not  merely  our  direct  measurements, 
go  towards  showing  that  oxygen  secretion  is  a  most  important 
physiological  factor,  not  merely  under  exceptional  circumstances, 
but  during  ordinary  life  at  sea  level.  It  is  probably  also  an  im- 
portant factor  under  pathological  conditions,  though  on  this  sub- 
ject our  knowledge  is  still  almost  a  blank,  owing  to  lack  of 
observations.  The  only  relevant  observations  are  those  of  Lorrain 
Smith.33  His  experiments,  when  due  allowance  is  made  for  the 
errors  already  referred  to  in  our  calculations,  showed  that  either 
a  rise  of  body  temperature  or  a  severe  infection  paralyzed  the 
power  of  oxygen  secretion  in  response  to  CO  poisoning.  When 
lung  inflammation  was  produced  by  exposing  the  animals  to  a 
high  pressure  of  oxygen  (see  Chapter  XII)  the  arterial  oxygen 
pressure  fell  to  values  which,  when  corrected,  are  much  below 
that  of  the  alveolar  air.  In  this  case  it  is  evident  that  not  only 
active  secretion,  but  also  diffusion  of  oxygen  inwards,  was  inter- 
fered with.  The  animals  were  incapable  of  muscular  exertion  and 
thus  showed  symptoms  similar  to  those  of  phosgene  poisoning,  as 
described  in  Chapter  VII. 

A  significant  determination  has  quite  recently  been  published 
by  Harrop34  of  the  percentage  saturation  of  human  arterial  blood 
with  oxygen,  first  during  rest,  and  then  just  after  exhausting 
work.  The  results  were  95.6  per  cent  during  rest,  and  85.5  per 
cent  just  after  the  exertion.  The  deficiency  found  in  the  blood  just 

32  Douglas  and  Haldane,  Journ.  of  Physiol.,  XLIV,  p.  337,  1913. 
88  Lorrain  Smith,  Journ.  of  Physiol.,  XXII,  p.  307,  1898. 
34  Harrop,  Journ.  of  Exper.  Med.,  XXX,  p.  246,  1919. 


248  RESPIRATION 

after  exertion  is  far  greater  than  could  be  accounted  for  by  ex- 
perimental errors. 

As  already  mentioned,  the  aerotonometer  experiments  of  Krogh 
indicated  that  the  arterial  CO2  pressure  is  the  same  as  that  of  the 
alveolar  air.  The  manner  in  which  the  respiratory  center  responds 
to  the  slightest  increase  or  diminution  in  the  alveolar  CO2  pres- 
sure, and  the  quantitative  correspondence  between  rise  in  alveolar 
CO2  pressure  and  response  of  the  respiratory  center,  point  most 
clearly  to  the  conclusion  that  within  pretty  wide  limits  there  is  no 
active  secretion  of  CO2  outwards  in  the  lung,  or  active  retention 
of  CO2  when  the  lungs  are  over-ventilated.  In  individual  experi- 
ments Bohr  obtained  results  which  seemed  to  point  to  active 
secretion  of  CO2  outwards.  The  latest  of  these  were  made  with 
Krogh's  small  aerotonometer;  but  Krogh  has  pointed  out  how 
easily  errors  may  arise  with  this  instrument;  and  in  view  of  all 
the  facts  I  think  his  criticism  of  Bohr's  experiments  is  probably 
correct. 

If  we  calculate,  by  Bohr's  method,  the  rate  of  diffusion  of  CO2 
from  the  alveolar  air  into  the  blood,  the  result  is  that  for  the  same 
difference  in  partial  pressure  CO2,  in  consequence  of  its  much 
greater  solubility,  must  diffuse  outwards  about  20  times  as  rapidly 
as  oxygen  diffuses  inwards.  Against  this,  however,  must  be  set  the 
fact  that  the  initial  difference  in  CO2  pressure  between  the  venous 
blood  and  alveolar  air  is  only  about  a  tenth  of  the  corresponding 
difference  in  oxygen  pressure.  On  balance,  however,  there  is  prob- 
ably little  hindrance,  even  during  hard  work,  to  the  establishment 
by  diffusion  of  practical  equilibrium  in  CO2  pressure  between  the 
alveolar  air  and  arterial  blood.  We  have  already  seen  that  the 
giving  off  of  CO2  in  the  lungs  is  dependent  in  great  part  on  the 
saturation  of  the  haemoglobin  with  oxygen.  Hence  the  giving  off 
of  CO2  is  to  a  large  extent  under  the  control  of  oxygen  absorp- 
tion, and  so  of  oxygen  secretion  when  this  occurs. 

Apart  from  this  there  seem  to  me  to  be  strong  reasons  for  sus- 
pecting that  although  active  secretion  of  CO2,  like  active  secretion 
of  oxygen,  does  not  occur  under  ordinary  conditions,  it  does  occur 
when  high  pressures  of  CO2  exist  in  the  arterial  blood,  and  the 
body  is  threatened  by  the  excess  of  CO2.  As  yet  there  is  no  direct 
evidence  on  this  subject ;  but  the  reasons  are  as  follows  :  ( I )  When 
a  small  volume  of  oxygen  is  rebreathed  as  long  as  possible,  or 
even  when  the  breath  is  held  as  long  as  possible  after  filling  the 
lungs  with  oxygen,  the  percentage  of  CO2  in  the  alveolar  air 
mounts  up  much  higher  and  more  rapidly  than  can  well  be  ac- 


RESPIRATION  249 

counted  for  from  any  probable  rise  in  the  pressure  of  CO2  in  the 
venous  blood.  Examples  of  experiments  in  this  direction  are  given 
in  the  paper  by  Christiansen,  Douglas,  and  myself.  (2)  It  ap- 
pears that  men  in  good  training  and  with  the  power  of  oxygen 
secretion  well  developed  are  capable  of  standing  a  much  higher 
percentage  of  CO2  in  the  inspired  and  alveolar  air  than  other 
men.  In  my  experience  with  self-contained  mine-rescue  apparatus, 
and  similar  devices,  I  have  often  been  struck  with  the  greater 
sensitiveness  to  CO2  of  myself  and  other  sedentary  workers  in 
comparison  with  men  in  good  physical  training,  although  nearly 
pure  oxygen  was  being  breathed.  These  observations  suggest  very 
strongly  that  along  with  the  power  of  oxygen  secretion  the  power 
of  secretion  of  CO2  is  developed  by  muscular  exertion.  (3)  In  the 
experiments  of  Paul  Bert35  on  the  blood  gases  when  increasingly 
high  percentages  of  CO2  were  breathed  by  animals,  it  appeared 
that  with  increase  in  the  CO2  percentage  the  CO2  in  the  arterial 
blood  often  showed  little  or  no  increase.  It  seems  very  dif- 
ficult to  explain  these  results  apart  from  active  secretion  of  CO2 
coming  into  play  progressively,  and  particularly  in  view  of  the 
experiments  of  Henderson  and  Haggard  on  the  increased  CO2- 
absorbing  capacity  of  the  blood  when  excess  of  CO2  is  breathed 
(Chapter  VIII). 

In  view  of  the  absence,  as  yet,  of  direct  measurements,  it  seems 
unnecessary  to  discuss  this  question  further;  but  I  may  point  out 
that  just  as  the  opponents  of  the  oxygen-secretion  theory  have 
been  mistaken  in  drawing  general  conclusions  from  experiments 
in  which  oxygen  secretion  was  either  absent  or  could  not  be  dem- 
onstrated, it  is  very  probable  that  they  have  been  equally  mistaken 
over  secretion  of  CO2.  Bearing  in  mind  Johannes  Miiller's  argu- 
ment as  to  the  analogy  between  secretory  activity  and  ordinary 
metabolic  processes,  it  seems  quite  likely  that  the  active  transport, 
not  only  of  oxygen,  but  also  of  CO2,  is  a  phenomenon  which  oc- 
curs in  all  living  cells. 

Not  only  do  oxygen  and  CO2  diffuse  through  the  lung  epithe- 
lium into  or  out  of  the  blood,  but  also  other  gases,  such  as  nitrogen, 
hydrogen,  methane,  carbon  monoxide,  etc.,  so  that  their  partial 
pressures  become  exactly  equal  in  the  body  and  the  alveolar  air. 
But  how  is  it  that  oxygen  is  sometimes  actively  secreted  inwards, 
and  that  the  oxygen  pressure  may  be  greater  in  the  blood  without 
the  oxygen  leaking  back  by  diffusion  into  the  alveolar  air  just  as 

"Paul  Bert,  La  Pression  barometrlque,  p.  985. 


250  RESPIRATION 

other  gases  leak  in  or  out?  We  must,  I  think,  suppose  that  the 
structure  of  the  alveolar  epithelium  is  not  homogeneous  but  may 
be  divided  into  a  reticulum  of  living  structure  and  a  plasma  filling 
the  interstices,  just  as  is  the  case  with  the  body  as  a  whole.  The 
diffusion  will  take  place  through  the  plasma,  while  the  living  sub- 
stance behaves  as  a  solid  towards  diffusion,  as  in  the  case  of  the 
secreting  cells  of  the  swim  bladder.  Not  only  oxygen  but  also 
other  gases  will  diffuse  through  the  plasma;  but  during  secretion 
of  oxygen  the  living  substance  behaves  like  the  protoplasm  of  the 
swim  bladder,  taking  up  oxygen  on  one  side  of  the  cell,  and  giv- 
ing it  off  at  a  higher  pressure  on  the  other.  The  oxygen  will  tend 
to  diffuse  backwards  if,  as  in  experiments  with  a  high  percentage 
of  CO,  the  oxygen  pressure  becomes  higher  in  the  blood  than  in 
the  alveolar  air;  but  some,  at  least,  of  this  oxygen  will  be  caught 
on  its  way  and  returned. 

This  general  conception  throws  light  in  other  directions.  For 
let  us  suppose  the  direction  of  the  oxygen  secretion  to  be  reversed, 
so  that  the  lung  epithelium,  instead  of  absorbing  oxygen,  hinders 
its  passage.  Nitrogen  and  other  inert  gases  will  still  be  able  to  pass 
inwards  freely  by  diffusion.  We  shall  thus  have  nitrogen  going 
through,  without  oxygen.  Now  let  us  suppose  that  the  epithelium 
has  an  excretory  function;  and  let  us  apply  the  general  concep- 
tions, above  set  forth,  to  the  glomerular  epithelium  of  the  kidney. 
We  can  imagine  the  living  substance  of  this  epithelium  holding 
back,  by  an  active  process,  all  the  normal  constituents  of  blood, 
particularly  water,  if  their  normal  diffusion  pressures  are  not  ex- 
ceeded, but  otherwise  letting  them  through.  All  the  known  facts 
seem  to  confirm  Bowman's  original  conclusion  that  the  water  of 
the  urine  is  usually  almost  entirely  separated  in  the  glomeruli.  It 
seems  also  clear  that  as  shown  by  Ludwig  and  his  pupils,  the 
process  of  separation  is  dependent  on  blood  pressure,  like  a  filtra- 
tion process.  If  we  suppose  that  the  passages  through  which  the 
liquid  is  filtered  are  not  permeable  by  the  proteins  of  the  blood, 
we  have  an  explanation,  as  pointed  out  by  Starling,  of  why  a  cer- 
tain minimum  blood  pressure  is  needed.  The  liquid  separated  might 
be  little  different  from  pure  water,  whereas  the  blood  plasma 
contains  salts  in  considerable  amount.  Such  a  liquid  could  not  be 
separated  by  simple  filtration,  and  numerous  other  facts  are 
against  the  simple  filtration  theory.  I  think  that  all  the  facts  con- 
form with  the  theory  that  the  glomerulus  is  a  filter,  but  with  a 
living  framework,  and  that  the  action  of  this  living  framework, 
is  to  pick  out  and  return  to  the  blood  what  belongs  to  its  normal 


RESPIRATION  251 

composition,  the  rest  being  allowed  to  pass.  In  this  process  the 
glomerular  epithelium  will  of  course  be  doing  work;  but  every 
living  tissue  seems  to  be  always  doing  work,  even  when  it  is  "rest- 
ing." During  a  glomerular  diuresis  there  may  be  no  extra  work  for 
the  epithelium  to  do,  and  it  will  simply  act  as  a  filter,  just  as  the 
lung  epithelium  during  rest  under  normal  conditions  acts  like  a 
nonliving  membrane.  Barcroft  and  Straub  have  shown  that  during 
certain  kinds  of  diuresis  there  is  no  increased  consumption  of 
oxygen  by  the  kidney,  and  therefore  presumably  no  work  done  by 
the  kidney  in  the  process  of  separation  of  the  extra  urine  formed.36 
It  is  probable  that  under  normal  conditions  a  pure  filtration 
diuresis  of  this  type  never  occurs  at  all;  but  the  possibility  of 
producing  it  experimentally  throws  much  light  on  the  mode  of 
action  of  the  glomeruli  and  also  of  the  lung  epithelium.  Possibly 
the  substances  carried  to  the  lungs  during  anoxaemia  act  in  the 
same  way  as  a  diuretic  drug  acts  on  the  kidneys. 

In  concluding  this  long  chapter  I  must  make  some  reference 
to  criticisms  which  have  been  made  on  our  experiments.  Part  of 
these  criticisms  are  the  evident  outcome  of  a  natural  conservative 
desire  to  save  some  remnant  of  the  old  mechanistic  theory  of 
glandular  secretion.  The  lungs  and  the  kidney  glomeruli  were 
the  last  remaining  strongholds  that  there  seemed  much  hope  of 
defending,  and  I  can  admire  the  spirit  which  has  animated  the 
defenders.  It  is  different,  however,  with  the  criticisms  made  by 
my  friend  Mr.  Barcroft  in  his  recent  book,37  as  he  fully  ac- 
knowledges the  difficulties  of  the  diffusion  theory  and  the  inherent 
probability  of  secretory  activity  in  the  lungs. 

He  bases  these  criticisms  on  the  work  of  his  pupil,  Mr.  Hart- 
ridge.  The  latter  devised  a  new  and  thoroughly  sound  method  of 
determining  the  percentage  saturation  of  the  blood  with  CO  by 
delicate  measurements  of  the  shifting  in  position  of  the  absorption 
bands  of  oxy-  and  CO-haemoglobin;  and  he  showed  clearly  that 
his  method,  although  it  requires  elaborate  apparatus,  is  capable 
of  giving  accurate  results.  Armed  with  this  method  he  proceeded 
to  repeat,  as  he  thought,  some  of  the  experiments  (not  yet  pub- 
lished except  in  a  short  abstract)  of  Douglas  and  myself  on  man. 
Unfortunately  he  modified  the  method  in  essential  respects,  neither 
taking  precautions  that  the  subject  was  breathing  a  constant  per- 
centage of  oxygen,  nor  using  whole  blood  in  the  saturator,  nor 
experimenting  in  a  way  calculated  to  elicit  any  evidence  of  active 

*°  Barcroft  and  Straub,  Journ.  of  Phystol.,  XLI,  p.  145,  1911. 
"  Barcroft,  The  Respiratory  Function  of  the  Blood,,  p.  204. 


252  RESPIRATION 

secretion  during  work.  His  experiments  did  not  appear  to  show 
any  active  secretion,  and  it  would  have  been  extraordinary  if 
they  had. 

I  now  come  to  the  main  point  of  Barcroft's  criticisms.  Hartridge 
had  at  first  calibrated  his  instrument  by  ascertaining  its  readings 
with  what  he  believed  to  be  known  mixtures  of  oxyhaemoglobin 
and  CO-haemoglobin.  He  subsequently  found  that  his  calibrations 
had  been  quite  incorrect;  and  in  order  to  secure  correct  calibration 
he  finally  had  recourse  to  the  very  tedious  method  of  pumping 
out  the  CO  and  oxygen  from  the  blood  mixture  after  adding 
ferricyanide,  and  determining  the  CO  and  oxygen  by  analysis, 
using  the  general  method  which  I  followed  in  originally  testing 
the  accuracy  of  the  ferricyanide  method  for  blood  gases.  In  his 
paper38  Hartridge  says  of  his  first  method  that  "experiments 
made  since  to  discover  the  cause  of  the  error  have  shown  that 
with  the  method  of  mixture  employed  complex  interactions  take 
place  between  the  two  portions  of  solvent."  Let  us  expand  this 
somewhat  mystic  statement.  He  was  working  with  blood  diluted 
with  water  to  about  a  twentieth.  One  portion  of  this  he  saturated 
with  CO,  and  another  portion  with  air.  These  were  then  mixed.  It 
was  apparently  expected  that  the  result  would  be  a  mixture  con- 
taining half  the  haemoglobin  saturated  with  CO  and  the  other 
half  with  oxygen.  Now  if  one  dilutes  blood  to  a  twentieth  and 
saturates  with  CO,  the  solution  will  contain  about  one  volume  of 
CO  in  combination  with  haemoglobin  to  two  and  one-half  in 
simple  solution ;  and  when  this  is  mixed  with  an  equal  proportion 
of  the  solution  saturated  with  air  the  CO  in  simple  solution  in  the 
first  part  will  straightway  combine  with  the  haemoglobin  in  the 
second  part,  and  turn  out  the  oxygen,  the  result  being  that  prac- 
tically the  whole  of  the  haemoglobin  combines  with  CO.  With 
the  method  first  adopted  by  Hartridge  it  was  clearly  impossible 
for  him  to  calibrate  his  instrument. 

Our  colorimetric  method  of  determining  the  saturation  of 
haemoglobin  with  CO  had  repeatedly  been  tested  against  mix- 
tures previously  prepared,  the  most  scrupulous  precautions  (de- 
scribed in  three  different  papers)  being,  however,  taken  to  avoid 
errors  arising  from  the  solubility  of  CO.  Barcroft,  however,  infers 
that  because  Hartridge's  calibration  failed  with  the  method  of 
mixtures,  ours  was  presumably  also  inaccurate :  whereas  Hart- 
ridge's  final  calibrations  were  made  with  the  blood  pump,  which 

38  Hartridge,  Journ.  of  Physiol.,  XLIV,  p.  9,  1912. 


RESPIRATION  253 

is  an  "objective  method,"  and  therefore  the  only  trustworthy  one. 
Hence,  Barcroft  argues,  Hartridge's  experiments,  so  far  as  they 
go,  furnish  the  only  reliable  evidence  about  oxygen  secretion,  as 
to  which  they  give  a  negative  result.  As  a  matter  of  fact  there  is 
not  a  shadow  of  doubt  that  our  method  of  testing  the  colorimetric 
method  was  at  least  as  exact  as  the  final  method  used  by  Hartridge. 

Barcroft's  reference  to  objective  methods  recalls  to  my  mind 
what  happened  when  Hartridge  came  to  Oxford  to  demonstrate 
his  method.  It  was  apparently  an  "objective  method,"  dependent, 
like  Hiifner's  spectrophotometric  method,  on  the  exact  positions 
of  absorption  bands  in  the  spectra  of  oxyhaemoglobin  and  CO 
haemoglobin — bands  of  which  the  "exact  positions"  can  be  quite 
easily  photographed.  A  solution  of  blood  was  prepared  for  dem- 
onstration; and  Hartridge,  the  late  Professor  Gotch,  and  I  went 
into  a  dark  room  and  proceeded  first  to  determine  the  zero  point 
on  the  scale  of  the  apparatus.  First  one,  and  then  the  others  of  us 
determined  the  zero  point.  But  the  results  were  all  different, 
though  each  one  of  us  always  got  the  same  result.  We  stood  there 
in  the  dark,  each  suspecting  the  others  of  want  of  accuracy,  but 
afraid  to  say  so.  Suddenly  the  truth  dawned  on  us.  Even  the 
position  of  an  absorption  band  is  subjective ! 

And  then,  if  our  ears  could  have  caught  it,  we  might  have 
heard  a  gentle  but  kindly  laugh.  It  came  from  a  Spirit  that  flits 
round  old  university  walls  and  even  wanders  sometimes  into 
laboratories.  It  was  the  Spirit  of  Humanism  that  laughed,  and  it 
always  laughs  when  men  find  out  with  Socrates  that  what  is  ob- 
jective is  also  subjective. 

Addendum..  Barcroft  and  his  associates39  have  recently  made  a 
very  carefully  planned  attempt  to  see  whether  any  evidence  of  oxy- 
gen secretion  could  be  obtained  by  analyses  of  the  arterial  blood. 
Barcroft  himself  was  the  subject  of  the  experiment,  and  he  re- 
mained for  a  week  in  a  respiration  chamber  in  which  the  oxygen 
percentage  was  gradually  lowered,  until  on  the  last  day  there  was 
only  about  1 1  per  cent  of  oxygen  in  the  air,  corresponding  to  an 
altitude  of  18,000  feet,  or  about  17,000  if  allowance  is  made  for 
the  presence  in  the  air  of  about  0.5  per  cent  of  CO2.  There  was 
thus  apparently  every  chance  of  acclimatization  occurring.  On  the 
other  hand  very  little  acclimatization  seems  to  have  actually  oc- 
curred, as  the  subject  was  very  unwell,  with  slight  rise  of  tempera- 

39  Barcroft,  Cooke,  Hartridge,  T.  and  W.  Parsons,  Journ.  of  PhysioL,  LIII, 
p.  450,  1920. 


254  RESPIRATION 

ture,  on  the  last  day  or  two,  and  was  in  a  fainting  condition  at  the 
end,  just  before  the  samples  of  arterial  blood  were  taken. 

Samples  of  arterial  blood  were  taken,  firstly  during  rest,  and 
later  during  work  on  a  bicycle  ergometer  of  about  380  kilogram- 
meters  per  minute,  which  would  increase  the  respiratory  exchange 
about  three  or  four  times.  The  haemoglobin  of  the  sample  during 
rest  was  found  to  be  88. 1  per  cent  saturated  with  oxygen.  Analyses 
of  the  arterial  blood  were  made,  both  by  the  ferricyanide  method 
and  with  the  pump,  and  agreed  closely.  Samples  of  alveolar  air 
were  also  taken,  and  part  of  the  arterial  blood  saturated  with  air 
of  about  the  same  composition.  The  saturation  of  the  haemoglobin 
of  this  blood,  when  corrected  for  the  slight  difference  in  oxygen 
pressure  between  the  air  in  the  saturator  and  the  sample  of 
alveolar  air,  was  found  to  be  91  to  92  per  cent,  which  is  distinctly 
higher  than  the  saturation  of  the  arterial  blood.  The  oxygen  pres- 
sure of  the  sample  of  alveolar  air  was,  however,  quite  unac- 
countably high.  It  was  68  mm.,  instead  of  about  45  mm.  which  was 
the  value  actually  found  in  a  determination  made  a  few  hours 
previously,  and  was  also  the  value  to  be  expected  from  the  curve 
shown  in  Figure  98  of  this  book.  Had  the  actual  alveolar  gas  pres- 
sures corresponded  with  those  of  the  sample,  the  respiratory  quo- 
tient would  have  been  about  2 ;  and  such  a  quotient  occurs  only 
during  forced  breathing,  which  could  not  have  occurred.  It  seems, 
therefore,  that  there  must  have  been  some  mistake  about  the  al- 
veolar sample;  but  what  this  was  is  far  from  clear.  If  the  actual 
alveolar  oxygen  pressure  had  been  about  45  mm.,  as  would  cor- 
respond to  the  alveolar  CO2  pressure,  the  oxygen  saturation  of 
the  blood  from  the  saturator  would  have  been  considerably  lower 
than  that  of  the  arterial  blood.  The  experiment  is  thus  inconclusive, 
apart  altogether  from  the  question  as  to  whether  the  subject  was 
acclimatized  at  all,  or  to  what  extent. 

The  experiment  during  work  is  much  more  consistent.  The 
arterial  haemoglobin  was  found  to  be  only  83.5  per  cent  saturated 
with  oxygen.  A  lower  saturation  during  work  of  the  character 
chosen  corresponds  well  with  all  our  observations  on  Pike's  Peak 
and  at  Oxford.  Unacclimatized  persons  became  very  blue  in  the 
face  on  Pike's  Peak  with  comparable  work ;  and  even  after  acclima- 
tization there  were  clear  indications  of  some  anoxaemia.  In  me,  for 
instance,  the  alveolar  oxygen  pressure  rose  about  8  mm.,  and  the 
alveolar  CO2  pressure  fell,  on  walking  at  4  miles  an  hour;  and 
this,  as  we  pointed  out,  indicated  arterial  anoxaemia.  The  haemo- 
globin of  the  blood  exposed  to  the  alveolar  air  in  the  saturator 


RESPIRATION  255 

gave  a  saturation  of  89.2  per  cent,  which  is  5.7  per  cent  higher 
than  the  saturation  of  the  arterial  blood.  This  result  furnishes  no 
evidence  of  secretion,  but  to  show  that  there  was  actually  no  secre- 
tion it  would,  I  think,  be  necessary  to  make  a  control  experiment 
on  a  person  who  had  spent  only  a  short  period  in  the  chamber,  and 
was  undoubtedly  unacclimatized. 

Barcroft  and  his  associates  consider  that  the  results  of  the 
experiments  were  against  the  secretion  theory.  In  this  I  cannot 
agree  with  them.  It  seems  to  me  evident  that  if  there  was  any 
acclimatization  in  these  experiments  it  was  very  imperfect,  and 
not  comparable  to  the  acclimatization  commonly  observed  at  high 
altitudes,  and  closely  studied  by  us  on  Pike's  Peak.  Acclimatization 
occurs  much  more  readily  in  certain  persons  than  in  others,  and 
seems  also  to  be  greatly  affected  by  accompanying  conditions.  An 
experiment  in  which  marked  acclimatization  occurred  in  myself 
in  a  respiration  chamber  was  referred  to  above.  On  endeavoring 
to  repeat  this  experiment  in  the  summer  of  1920  there  was  no 
effective  acclimatization,  and  on  account  of  severe  symptoms  of 
anoxaemia,  accompanied  by  blueness  of  the  lips,  etc.,  I  had  to 
stop  before  the  oxygen  pressure  had  fallen  to  quite  as  low  a  point 
as  on  Pike's  Peak,  or  to  nearly  as  low  a  point  as  in  the  previous 
experiment  where  no  pathological  signs  of  anoxaemia  were  pro- 
duced. It  was  about  a  week  before  I  recovered  from  the  effects  of 
this  unsuccessful  experiment.  The  weather  was  hot,  and  the 
chamber  correspondingly  uncomfortable.  I  was  also  several  years 
older.  In  this  experiment  my  arterial  blood  was  analysed  by  Pro- 
fessor Meakins,  who  found  the  haemoglobin  to  be  considerably 
below  its  normal  saturation  with  oxygen.  There  was  evidently 
little  or  no  acclimatization. 

I  should  like  to  correct  here  one  or  two  misunderstandings  which 
occur  in  the  paper  of  Barcroft  and  his  associates.  Through  a  mis- 
reading of  the  paper  by  Douglas  and  myself  he  concluded  that 
on  lowering  the  oxygen  pressure  of  the  inspired  air  to  what  cor- 
responded to  about  the  oxygen  pressure  on  Pike's  Peak  we  found 
in  a  short  experiment  at  Oxford  that  by  the  carbon  monoxide 
method  the  arterial  oxygen  pressure  was  70  mm.  above  the  al- 
veolar oxygen  pressure.  The  actual  difference  was  only  trifling 
(about  8  mm.),  as  shown  in  the  table  reproduced  above.  It  re- 
quired prolonged  acclimatization  to  produce  as  great  a  difference 
as  even  35  mm.  There  is  also  a  misunderstanding  as  to  our  experi- 
ments on  the  effects  of  work.  Though  we  made  no  observations  by 
the  carbon  monoxide  method  on  the  effects  of  work  such  as  was 


256  RESPIRATION 

employed  by  Barcroft,  all  the  other  observations  referred  to  in 
the  present  chapter  tend  to  show  that  except,  perhaps,  when  physi- 
cal training  or  acclimatization  is  very  effective,  the  arterial  oxygen 
saturation  during  such  work  is  lower  than  during  rest. 

Clear  evidence  is  brought  forward  by  Barcroft  and  his  associ- 
ates that  no  appreciable  loss  of  dissociable  oxygen  occurs  in  ar- 
terial blood  which  is  allowed  to  stand  for  a  short  time.  In  the 
Pike's  Peak  report  we  concluded  that  such  a  loss  probably  occurs. 
The  chief  reason  for  this  conclusion  was  that  the  aerotonometer 
always  gives  a  lower  oxygen  pressure  than  that  deduced  on  the 
diffusion  theory  from  the  alveolar  oxygen  pressure,  or  indicated 
by  the  carbon  monoxide  method  during  rest  under  ordinary  baro- 
metric pressure.  As  explained  above,  however,  there  is  now  an- 
other and  very  clear  explanation  for  this ;  and  since  the  investiga- 
tion by  Meakins,  Priestley,  and  myself  on  the  effects  of  shallow 
breathing  I  have  altogether  ceased  to  believe  in  the  presence,  to 
any  extent  which  would  upset  a  blood-gas  or  aerotonometer  de- 
termination, of  "reducing  substances"  in  blood.  I  am  in  entire 
agreement  with  Barcroft's  criticism  of  the  old  experiments  by 
which  Pfliiger  believed  that  he  had  demonstrated  the  existence 
of  reducing  substances  in  fresh  arterial  blood.  It  may  also  be  men- 
tioned here  that  in  some  unpublished  experiments  Douglas  and  I 
were  unable  to  obtain  any  evidence  by  blood-gas  analysis  of  the 
presence  of  reducing  substances,  even  in  blood  which  was  com- 
pletely reduced  by  prolonged  stoppage  of  the  circulation  in  the 
arm. 


CHAPTER  X 
Blood  Circulation  and  Breathing. 

ALTHOUGH  it  does  not  fall  within  the  scope  of  this  book  to  deal 
in  detail  with  the  physiology  of  the  circulation,  yet  the  connection 
between  breathing  and  circulation  is  so  specially  intimate  that  a 
chapter  must  be  devoted  to  this  subject.  Physiology  is  most  em- 
phatically not  a  subject  which  can  be  divided  off  into  water-tight 
compartments. 

We  have  seen  that  it  is  with  the  composition  of  the  arterial 
blood  that  breathing  is  essentially  correlated;  but  it  has  also  been 
shown  in  successive  chapters  that  the  amount  and  composition  of 
the  blood  returning  from  the  tissues  to  the  lungs  play  a  most  es- 
sential part  in  determining  the  composition  of  the  arterial  blood, 
and  are  thus  intimately  correlated  with  breathing.  If,  moreover, 
the  blood  supply  to  the  brain  and  other  tissues  is  insufficient,  or 
the  blood  is  abnormal  in  composition,  the  breathing  is  affected  in 
various  ways.  On  the  other  hand  circulation  is  intimately  de- 
pendent on  breathing.  If  the  breathing  is  hindered  the  circulation 
is  quickly  affected;  and,  as  Yandell  Henderson  was  the  first  to 
show,  excessive  breathing  brings  about  failure  of  the  circulation. 
Thus  we  cannot  at  all  fully  understand  how  the  breathing  is  regu- 
lated and  what  part  it  is  playing  unless  we  understand  the  dis- 
tribution of  the  circulating  blood  and  the  means  by  which  its 
composition  in  the  tissue  capillaries  is  regulated. 

It  seems  evident  that  the  most  urgent  and  immediate  need  for 
an  adequate  blood  supply  to  any  part  of  the  body  arises  from  the 
necessity  for  a  continuous  supply  of  fresh  oxygen.  If  the  supply 
of  oxygen  to  the  arterial  blood  is  cut  off  in  a  warm-blooded  animal 
by  placing  it  in  nitrogen  or  hydrogen,  loss  of  consciousness  oc- 
curs as  soon  as  the  store  of  oxygen  in  the  lungs  and  venous  blood 
is  washed  out.  In  man  eight  or  ten  breaths  suffice  for  this  during 
rest,  and  still  fewer  breaths  during  exertion.  In  very  small  ani- 
mals, with  their  rapid  breathing  and  circulation,  two  or  three 
seconds  are  sufficient;  and  a  few  seconds  afterwards  the  heart  is 
paralyzed  also.  The  important  effects  of  even  a  slight  diminution 
in  the  pressure  of  oxygen  in  the  arterial  blood  have  been  made 
clear  in  preceding  chapters. 


258  RESPIRATION 

A  second,  but  somewhat  less  urgent,  need  is  for  a  continuous  re- 
moval of  carbonic  acid  or  any  other  acid  product  formed  in  the 
tissues.  We  can  probably  express  this  generally  as  a  need  for  pre- 
venting an  abnormal  proportion  of  hydrogen  ions  to  hydroxyl 
ions.  The  effect  on  the  central  nervous  system  of  a  sudden  flooding 
with  CO2,  without  deficiency  of  oxygen,  is  almost  as  striking, 
though  not  so  immediately  dangerous  to  life,  as  the  effect  of 
deprivation  of  oxygen.  The  results  of  even  a  slight  variation  in 
arterial  CO2  pressure  have  often  been  referred  to  already. 

Other  conditions  in  the  blood  besides  the  diffusion  pressures  of 
oxygen  and  CO2  or  other  acid  products  are  just  as  important  to 
life.  For  instance  there  are  the  diffusion  pressure  of  water  (inac- 
curately identified  with  osmotic  pressure)  and  the  diffusion  pres- 
sures of  the  ions  of  various  inorganic  salts,  on  the  importance  of 
which  the  investigations  of  Ringer  and  many  others  have  thrown 
much  light.  But  none  of  these  values  vary  in  the  same  rapid 
manner  as  the  diffusion  pressures  of  oxygen  and  CO2  do ;  and  of 
ordinary  nutrient  substances  present  in  blood,  the  tissues  them- 
selves appear  to  possess  a  store  which  can  be  drawn  on  if  the 
supply  from  the  blood  fails  for  a  time.  The  results  of  perfusion 
experiments  continued  with  the  same  blood  indicate  that  if  only 
the  blood  is  properly  aerated  it  continues  for  a  very  long  time  to 
support  life  in  the  tissues. 

It  would  seem,  therefore,  that  the  regulation  of  circulation 
through  the  tissues  must  in  the  main  be  determined  in  correlation 
with  the  need  for  supplying  oxygen  and  removing  CO2.  There 
are  evidently,  however,  cases  where  some  other  factor  determines 
the  circulation  rate.  For  instance,  the  skin  circulation  is  de- 
termined to  a  large  extent  in  relation  to  the  regulation  of  body 
temperature;  and  the  circulation  through  an  actively  secreting 
gland  is  probably  determined  to  a  considerable  extent  in  corre- 
lation with  local  excess  or  deficiency  of  water  or  dissolved  solids. 

We  can  form  a  general  idea  as  to  what  changes  in  gaseous 
composition  determine  the  circulation  rate  through  the  tissues  if 
we  compare  the  arterial  blood  with  the  mixed  venous  blood  re- 
turning to  the  lungs.  As  regards  this  point,  analyses  showing  the 
difference  in  composition  have  already  been  quoted  in  Chapter  V, 
and  indicate  that,  in  the  animals  experimented  on,  the  blood  in 
its  passage  through  the  tissues  had  lost  about  a  third  of  its  avail- 
able oxygen,  and  gained  the  amount  of  CO2  which  would  cor- 
respond to  the  loss  of  oxygen  when  allowance  is  made  for  the 
existing  respiratory  quotient  of  the  animal.  If  we  applied  these 


RESPIRATION  259 

results  to  man,  and  interpreted  them  in  the  light  of  the  thin  line 
in  the  dissociation  curves  of  oxyhaemoglobin  shown  in  Figure  28 
(assuming  that  the  haemoglobin  of  arterial  blood  is  95  per  cent 
saturated)  and  the  thick  line  in  the  corresponding  curve  for  CO2 
(Figure  26)  it  would  appear  that  the  average  pressure  of  oxygen 
in  the  venous  blood  is  about  5.2  per  cent  of  an  atmosphere,  or 
40  mm.  of  mercury,  and  the  average  pressure  of  CO2  about  47  mm. 
The  experiments  were,  however,  made  on  animals,  while  the  dis- 
sociation curves  (the  only  accurately  determined  ones)  are  for 
human  blood.  Moreover  the  animals,  owing  to  operative  disturb- 
ances, anaesthetics,  etc.,  were  more  or  less  under  abnormal  con- 
ditions. Hence  the  inferences  -just  drawn  are  mere  approxima- 
tions. The  very  great  variability  in  the  CO2  content  of  the  samples 
of  arterial  blood  from  animals  of  the  same  species,  as  compared 
with  the  constancy  of  CO2  content  in  the  case  of  man  under  normal 
resting  conditions,  is  in  itself  very  significant.  The  history  of  the 
investigations  detailed  in  the  preceding  chapters  is  sufficient  to 
warn  us  of  the  necessity  for  reaching  more  than  rough  approxima- 
tions in  physiological  investigation,  and  for  expecting  that  physio- 
logical regulation  of  the  circulation  may  turn  out  to  be  something 
just  as  delicate  and  definite  as  regulation  of  respiration.  It  is  to 
measurements  in  man,  rather  than  in  animals,  that  we  must  look 
for  information  of  sufficient  physiological  accuracy,  just  as  it  has 
been  through  measurements  in  man  that  our  definite  information 
as  to  the  regulation  of  breathing  has  been  obtained. 

The  difficulty  as  regards  human  experiments  has  till  quite 
recently  been  that  of  suitable  methods.  We  can  easily  measure 
the  blood  pressure,  pulse  rate,  etc.,  in  man;  but  the  information 
thus  obtained  is  extremely  limited  in  value  and  almost  impossible 
to  interpret  satisfactorily  in  the  absence  of  information  as  to  the 
rate  of  blood  flow.  Direct  measurements  of  the  rate  of  blood  flow 
in  animals  have  been  carried  out  by  means  of  the  Ludwig 
"Strohmuhr"  and  the  improved  forms  of  it  which  have  been 
applied  to  measuring  the  blood  flow  through  the  aorta;  but  the 
operative  disturbance  is  far  too  serious  to  allow  of  sufficiently 
definite  results  being  obtained.  Valuable  information  of  a  rough 
kind  was  obtained  by  Zuntz  and  Hagemann1  in  experiments  in 
which  the  gases  of  the  venous  and  arterial  blood  were  determined 
in  horses,  along  with  the  total  respiratory  exchange,  during  rest 
and  work.  These  experiments  seemed  to  show  clearly  that  the 

1  Zuntz  and  Hagemann,  LancLwirtsch.  Jahrb.,  27,  Supplem.  Bd.  Ill,  1898. 


260 


RESPIRATION 


general  circulation  rate  is  considerably  increased  during  muscular 
work,  so  that,  in  spite  of  the  enormous  increase  in  consumption  of 
oxygen  and  production  of  CO2  in  the  body,  there  is  still  a  good 
deal  of  oxygen  in  the  venous  blood. 

Other  very  interesting  experiments  were  made  on  man  by 
Loewy  and  von  Schrotter.2  They  succeeded  in  introducing  a 
modified  Pfliiger  lung  catheter  (Figure  68)  into  a  branch  bron- 
chus or  one  of  the  two  main  bronchi  in  man.  The  supply  of  fresh 


Figure  68. 

Lung-catheter  as  used  by  Loewy  and  von  Schrotter.  The  lung-catheter  con- 
sists of  a  central  inner  tube  open  at  the  lower  end,  and  an  outer  tube  ending 
below  in  a  distensible  bulb  which  can  be  blown  up  by  the  rubber  bag  when  the 
end  of  the  catheter  is  placed  in  position  in  a  bronchus.  By  means  of  the  syringe 
and  glass  sampling  tube  a  sample  of  gas  from  beyond  the  bulb  can  be  collected 
over  mercury  free  of  air. 

air  to  the  corresponding  part  of  a  lung,  or  whole  lung,  was  thus 
completely  cut  off  and  remained  so  for  long  periods.  The  breath- 
ing, however,  went  on  quite  quietly  and  naturally,  just  as  before, 
even  though  all  the  air  usually  distributed  to  the  two  lungs  was 
going  to  only  one  lung.  It  is  very  significant  that  so  little  dis- 
turbance in  breathing,  etc.,  was  produced;  but  the  fact  is  quite 
easily  intelligible  now  in  the  light  of  the  preceding  chapters.  The 

2  Loewy  and  von  Schrotter,  Die  Blutcirculation  beim  Menschen,  1905. 


RESPIRATION  261 

lung  which  remained  connected  with  fresh  air  was  receiving 
much  more  fresh  air  than  usual,  so  that  the  proportion  of  CO2 
in  the  arterial  blood  from  this  lung  would  be  reduced  practically 
in  proportion  to  its  increased  ventilation.  This  blood  would  mix 
with  the  venous  blood  from  the  other  lung,  and  in  this  way  form 
a  mixture  in  which  the  proportion  of  CO2  was  about  normal.  The 
arterial  blood  from  the  ventilated  lung  would,  in  virtue  of  the 
higher  pressure  of  oxygen  and  lower  pressure  of  CO2,  contain 
slightly  more  oxygen  than  usual,  while  the  blood  from  the  un- 
ventilated  lung  would  contain  considerably  less.  The  result  would 
be  a  mixture  containing  an  abnormally  low  proportion  of  oxy- 
gen, but  not  sufficiently  low  to  cause  any  marked  immediate  dis- 
turbance. Even  with  a  whole  lung  blocked  off,  the  haemoglobin 
of  the  mixed  arterial  blood  would  be  at  least  85  per  cent  saturated 
with  oxygen  instead  of  95  per  cent,  so  that  the  effect  on  the  breath- 
ing would  be  no  greater  than  the  probable  effect,  hardly  notice- 
able at  the  time,  of  breathing  air  containing  14  per  cent  of  oxy- 
gen, or  ordinary  air  at  a  height  of  about  1 1,000  feet. 

Analyses  of  the  air  in  the  blocked  lung  showed  that  after  a 
comparatively  short  interval  of  time  the  percentages  of  oxygen 
and  CO2  became  steady,  and  were,  in  different  individuals,  about 
5.3  per  cent  of  oxygen  and  6.0  per  cent  of  CO2,  corresponding 
respectively  to  37.5  mm.  and  42  mm.  These  values  are  evidently 
the  pressures  of  oxygen  and  CO2  in  the  venous  blood.  The  low 
value  of  the  venous  CO2  pressure  was  quite  unintelligible  at  the 
time,  since  the  average  arterial  CO2  pressure  is  about  40  mm.  as 
shown  above.  The  experiments  of  Christiansen,  Douglas,  and 
myself  (Chapter  V)  showed,  however,  that  the  true  venous  CO2 
pressure  is  in  reality  only  a  little  higher  than  the  arterial  CO2 
pressure;  and  if  we  allow  for  the  fact  that  the  breathing  was 
presumably  slightly  increased  by  the  stimulus  of  want  of  oxygen 
the  result  is  just  what  might  be  expected.  The  venous  oxygen 
pressure  would  be  somewhat  lower  than  usual,  since  the  arterial 
blood  was  incompletely  saturated  with  oxygen.  Hence  both  the 
oxygen  pressure  and  the  CO2  pressure  would  be  below  normal. 
The  results  of  these  experiments  were  nevertheless  of  the  highest 
interest. 

It  is  evident  that  if  by  any  means  we  can  measure  the  rate  of 
blood  flow  through  the  lungs,  and  at  the  same  time  measure  the 
intake  of  oxygen  and  discharge  of  CO2  from  the  blood,  we  can 
calculate  how  much  oxygen  a  given  volume  of  the  blood  gains, 
and  how  much  CO2  it  loses,  in  the  lungs ;  and  in  this  way  we  can 


262  RESPIRATION 

indirectly  calculate  how  far  the  gain  and  loss  vary  under  different 
conditions.  A  rough  method  devised  by  Yandell  Henderson  for 
measuring  the  relative  rates  of  the  blood  flow  was  used  in  the 
Pike's  Peak  expedition,  and  served  to  indicate  that  the  rate  of 
blood  flow  remained  practically  normal  in  spite  of  the  great  alti- 
tude. Another  method,  the  principle  of  which  was  tried,  though 
without  success,  by  Henderson  on  Pike's  Peak,  was  about  the  same 
time  independently  worked  out  and  extensively  used  by  Krogh 
and  Lindhard  at  Copenhagen.3  This  method  gives  absolute  and  not 
merely  relative  results.  The  principle  of  the  method  is  that  the 
lungs  are  filled  by  a  very  deep  breath  with  a  mixture  containing  a 
considerable  percentage  of  nitrous  oxide,  a  gas  which  is  very  solu- 
ble in  blood.  A  sample  of  alveolar  air  is  taken  after  an  interval  of 
five  seconds  to  allow  the  lung  tissue  to  become  saturated  with  the 
nitrous  oxide,  and  after  a  further  interval  during  which  the  breath 
is  held,  another  alveolar  sample.  By  determining  the  nitrous 
oxide  in  the  two  samples,  and  also  the  total  volume  of  gas  in  the 
lungs,  we  find  out  how  much  nitrous  oxide  has  been  absorbed. 
Knowing  the  solubility  of  nitrous  oxide  in  blood,  and  assuming 
also  that  the  blood  leaving  the  lungs  is  fully  saturated  with  nitrous 
oxide  to  the  existing  partial  pressure  of  the  gas,  we  can  calculate 
from  the  loss  of  nitrous  oxide  how  much  blood  has  passed  through 
the  lungs  in  the  given  time  interval.  The  experiment  must  be 
carried  out  so  rapidly  that  the  venous  blood  continues  to  be  free 
of  nitrous  oxide. 

There  are  various  sources  of  probable  error  in  this  method,  but 
in  the  hands  of  Krogh  and  Lindhard  it  gave  fairly  consistent 
results.  They  found  that  during  rest  the  amount  of  blood  circula- 
ting through  the  lungs  of  an  adult  man  varies  from  about  2.8 
to  5  liters  per  minute,  and  that  the  arterial  blood  loses  about  30 
to  60  per  cent  of  its  available  oxygen  on  an  average,  and  during 
considerable  work  about  50  to  70  per  cent.  The  following  table 
gives  calculated  volumes  of  blood  passing  through  the  lungs,  and 
calculated  percentage  losses  in  the  available  oxygen  of  the  blood 
as  it  passes  round  the  tissues. 

It  will  be  seen  that,  allowing  for  the  fact  that  the  haemoglobin 
of  arterial  blood  is  only  95  per  cent  saturated  with  oxygen,  the 
haemoglobin  of  the  venous  blood  was  apparently  only  38  per  cent 
and  53  per  cent  saturated  in  the  two  resting  experiments.  The 
flow  of  blood  through  the  lungs  during  work  appeared  to  be  as 

1  Krogh  and  Lindhard,  Skand.  Arch.  /.  Physiol.,  XXVII,  p.  100,  1912. 


RESPIRATION  263 

much  as  six  times  as  great  as  during  rest.  As  the  pulse  rate  only 
went  up  to  about  double  the  normal,  the  volume  of  blood  expelled 
from  the  heart  at  each  systole  must,  if  these  results  were  reliable, 
have  been  trebled.  This  would  be  just  as  striking  an  increase  as 
occurs  in  the  depth  of  breathing  during  muscular  work.  The  values 
for  utilization  of  the  available  oxygen  of  the  arterial  blood  are 


Subject                         Work  in  kg.m. 

Calculated,  blood- 

Percentage  utilization 

per  minute 

flow  —  Liters  per 

of  available  O»  of 

•minute 

arterial  blood, 

J.  L.                                         0 

2.8 

60 

458 

9.8 

73 

i  minute  ajter 

•work 

4-45 

44 

A.  K.                            o 

2.92 

46 

446 

16.0 

47 

552 

17.6 

Si 

not  very  far  from  those  obtained  in  the  horse  by  Zuntz  and 
Hagemann,  but  do  not  agree  at  all  well  with  those  of  Loewy  and 
von  Schrotter  in  man.  In  the  case  of  six  experiments  on  different 
individuals  where  approximate  data  were  available  the  latter 
observers  calculated  a  utilization  of  rather  less  than  20  per  cent 
during  rest. 

During  or  since  the  war  several  other  observers  have  used  the 
method  of  Krogh  and  Lindhard,  and  obtained  more  or  less  similar 
results.  These  observers  include  Boothby,3A  as  well  as  Newburgh 
and  Means3B  in  America.  Lindhard30  has  also  published  a 
number  of  additional  results,  which  give,  on  the  whole,  a  distinctly 
higher  rate  of  circulation,  and  lower  percentage  utilization  of 
oxygen,  during  rest. 

The  subject  had  meanwhile  been  approached  by  a  quite  different 
method  by  Yandell  Henderson.4  He  used  dogs  for  his  experi- 
ments, and  placed  a  recording  plethysmograph  round  the  heart 
after  removing  the  pericardium.  By  this  method  he  found  that 
the  volume  of  blood  discharged  per  heartbeat  was  approximately 
the  same,  whether  the  heart  was  beating  faster  or  slower.  Thus 
within  wide  limits  the  volume  of  blood  discharged  per  minute 

3ABoothby,  Amer.  Journ.  of  Physiol.,  XXXVIII,  p.  383,   1915. 

8B  Newburgh  and  Means,  Journ.  of  Pharm.  and,  Exp.  Therap.,  VII,  p.  4,  1915. 

30  Lindhard,  PfHiger's  Archiv. 

4  Yandell  Henderson,  Amer.  Journ.  of  Physiol.,  XVI,  p.  325,   1906. 


264  RESPIRATION 

appeared  to  depend  almost  entirely  on  the  pulse  rate.  He  concluded 
that  under  normal  conditions  the  heart  is,  practically  speaking, 
always  adequately  filled  during  diastole,  although  under  abnormal 
conditions  the  filling  may  become  inadequate — for  instance  when 
the  carbon  dioxide  of  the  blood  is  greatly  reduced  by  excessive 
artificial  respiration.  If  we  apply  Henderson's  conclusions  to  man 
it  is  evident  that  they  cannot  be  reconciled  with  those  of  Krogh 
and  Lindhard.  On  Henderson's  theory  the  increased  absorption  of 
oxygen  and  discharge  of  CO2  from  the  blood  passing  through  the 
lungs  during  muscular  exertion  must  be  due  to  a  very  large  ex- 
tent to  greater  utilization  of  the  oxygen  in  the  blood  passing 
round  the  body,  and  a  corresponding  increase  in  its  charge  of  CO2. 
The  rate  of  circulation  can  only  be  increased  in  proportion  to  in- 
creased pulse  rate,  the  discharge  of  blood  per  systole  remaining 
about  the  same. 

There  is  no  question  that  the  systolic  discharge  may,  at  least 
under  abnormal  conditions,  vary  enormously.  This  was  very 
clearly  shown  by  the  experiments  of  Starling  and  Patterson,5  with 
a  "heart-lung  preparation" — i.e.,  a  preparation  in  which  the 
only  circulation  was  through  the  lungs  and  heart,  the  lungs  being 
ventilated  so  as  to  insure  full  oxygenation  of  the  blood.  By  vary- 
ing the  venous  blood  pressure,  the  systolic  discharge  could  be 
varied  tenfold,  without  any  variation  in  the  pulse  rate.  It  does  not 
follow,  however,  that  there  are  corresponding  variations  in  systolic 
discharge  in  normal  men  and  animals  with  the  organic  regulation 
of  circulation  not  thrown  out  as  in  the  case  of  a  heart-lung  prepa- 
ration. 

In  the  nitrous  oxide  method  there  are  various  sources  of  pos- 
sible very  serious  error  which  can  hardly  be  discussed  in  detail 
here.  In  order  to  get  a  more  direct  and  accurate  insight  into  the 
venous  gas  pressures  and  their  relation  to  blood  flow,  a  new 
method  was  introduced  by  Christiansen,  Douglas,  and  myself.6 
In  the  first  application  of  this  method  we  simply  determined  the 
CO2  pressure  of  the  venous  blood  after  oxygenation  but  without 
its  losing  any  CO2.  As  we  had  already  discovered  (see  Chapter 
V),  this  pressure  is  higher  by  an  easily  calculable  amount  than 
that  for  the  unoxygenated  venous  blood.  Mixtures  containing 
about  the  required  percentage  of  CO2  were  prepared  by  adding 
CO2  to  air.  A  deep  breath  of  one  of  these  mixtures  was  taken  in 

5  Starling  and  Patterson,  Journ.  of  Physwl.,  XLVIII,  p.  357,  1914. 
9  Christiansen,    Douglas,   and  Haldane,  Journ.   of  Phystol.,   XLVIII,   p.   244, 
1914. 


RESPIRATION  265 

after  previously  expiring  deeply.  After  two  seconds  part  of  the 
air  in  the  lungs  (about  il/2  liters)  was  expired,  so  as  to  obtain  a 
sample  of  alveolar  air.  The  rest  of  the  breath  was  held  for  five 
seconds  and  a  second  sample  of  alveolar  air  was  then  taken.  If 
these  two  samples  gave  practically  the  same  percentage  of  CO2, 
the  CO2  in  the  alveolar  air  was  evidently  in  pressure  equilibrium 
with  the  CO2  of  the  oxygenated  venous  blood.  If  too  much  CO2 
were  present  in  the  alveolar  air  the  second  sample  would  contain 
less  CO2  than  the  first,  and  if  too  little,  more.  We  were  thus  using 
the  whole  of  both  lungs  as  an  aerotonometer.  For  any  particular 
person  it  was  easy  to  find  the  mixture  which  gave  equilibrium. 
With  the  help  of  Figure  26  (Chapter  V)  we  could  then  calculate 
the  CO2  content  of  the  venous  blood  and  the  true  value  of  the 
venous  CO2  pressure.  We  could  also  calculate  how  much  CO2  the 
blood  had'  taken  up  in  passing  round  the  body  if  we  knew  the 
normal  alveolar  CO2  pressure.  The  following  table  shows  the 
results  obtained  during  complete  rest  in  a  sitting  position  with  the 
four  subjects  investigated. 


Subject 

Arterial  COz  pressure 

Venous  COz  pressure 

Difference 

in  mm.  Hg. 

in  mm.  H  g. 

J.  C. 

34-9 

41.8 

6.9 

J.  S.  H. 

40.6 

45-6 

5-0 

C.  G.  D. 

39-7 

44-4 

4-7 

J.  G.  P. 

40.4 

45-1 

4-7 

Mean 

38.9 

44-2 

5-3 

Reference  to  Figure  26  shows  that  on  an  average  the  venous 
blood  had  only  taken  up  about  24  per  cent  of  the  CO2  which  it 
would  have  taken  up  if  all  its  available  oxygen  had  been  used  up. 
Hence  the  blood  had  only  lost  about  24  per  cent  of  its  oxygen  in 
passing  round  the  circulation;  and  in  the  three  male  subjects  the 
proportion  lost  was  only  about  21  to  22  per  cent.  This  indicates  a 
much  faster  circulation  rate  during  rest  than  the  nitrous  oxide 
method  had  shown. 

At  the  outbreak  of  war,  Dr.  Douglas  and  I  were  engaged 
in  carrying  these  experiments  further;  but  as  he  volunteered  at 
once  for  active  service  they  were  interrupted;  and  owing  to  the 
disorganization  following  the  war  they  are  not  yet  completed, 
though  I  was  able  to  carry  them  on  up  to  a  certain  point  with 
help  from  Dr.  Mavrogardato,  and  to  communicate  a  number  of 


266  RESPIRATION 

results  to  the  Physiological  Society  in  1915.  We  had  been  engaged 
in  measuring  directly  both  the  true  venous  CO2  pressure  and 
oxygen  pressure  just  after  forced  breathing,  so  as  to  discover  the 
effects  of  lowered  CO2  pressure  on  the  circulation.  We  found  that 
the  apparent  venous  oxygen  pressures  were  incredibly  high — 
70  mm.  or  even  more.  On  further  investigation  it  became  evident 
that  after  a  single  deep  expiration,  followed  by  a  single  deep  in- 
spiration of  the  gas  mixture,  the  air  in  the  alveoli  was  not  properly 
mixed.  At  the  end  of  the  forced  breathing  there  would  be  nearly 
20  per  cent  of  oxygen  in  the  alveolar  air.  With  one  deep  inspira- 
tion of  the  mixture,  the  air  in  the  air-sac  system  of  alveoli  was 
mingled  with  air  from  the  inspired  mixture,  but  an  even  mixture 
in  all  parts  of  the  alveolar  system  was  not  obtained,  so  that  the 
air-sac  alveoli  contained  considerably  more  oxygen  than  the  rest 
of  the  alveoli.  As  a  consequence  the  second  alveolar  air  sample, 
taken  more  exclusively  from  the  air-sac  alveoli,  contained  more 
oxygen  than  the  first,  in  spite  of  the  fact  that  it  had  remained 
longer  in  the  lungs.  It  was  evidently  necessary,  therefore,  to  take 
two  or,  in  the  case  of  forced  breathing,  three  successive  deep 
breaths  of  the  mixture  before  holding  the  breath  and  taking 
the  samples.  When  this  was  done  the  results  were  quite  consistent, 
and  showed  that  the  venous  CO2  pressures  as  determined  directly 
during  rest  confirmed  the  calculated  values  previously  obtained; 
while  the  venous  oxygen  pressures,  when  interpreted  in  the  light 
of  the  thin-line  curve  of  Figure  28,  corresponded  very  closely 
with  the  percentage  oxygen  loss  of  the  blood  as  calculated  indi- 
rectly from  the  venous  CO2  pressure.  Moreover,  not  only  the 
venous  CO2  pressure,  but  also  the  venous  oxygen  pressure,  was 
considerably  lower  at  the  end  of  forced  breathing. 

The  following  are  examples  of  two  typical  experiments  carried 
out  on  myself  at  the  end  of  ten  minutes'  rest  on  a  chair. 

No.  i,  26/2/15.  Bar.  762  mm. 

Mixture  used  contained  6.21  per  cent  of  CO2  and  5.73  per  cent  of 
oxygen. 

First  alveolar  sample  2"  after  last  deep  inspiration,  6.43  per  cent 
of  CO2  and  6.18  per  cent  of  oxygen. 

Second  alveolar  sample  5"  after  first  sample,  6.47  per  cent  of  CO2 
and  6.22  per  cent  of  oxygen. 

Therefore  venous  CO2  pressure  =  6.47  per  cent  =  46.16  mm.  and 
oxygen  pressure  6.22  per  cent  =  44.5  mm. 

Normal  alveolar  CO2  percentage  (mean  of  inspiratory  and  expira- 
tory samples)  5.64  per  cent  =  40.3  mm. 


RESPIRATION  267 

Metabolism  (by  Douglas  Bag  method)  =  330  cc.  of  CO2  and  379 
cc.  of  oxygen  (at  o°  and  760  mm.)  per  minute. 

As  the  venous  CO2  pressure  was  6.O  mm.  above  the  arterial, 
the  blood  (calculating  from  Figure  26)  had  gained  4.2  per  cent 
by  volume  of  CO2.  Hence  the  circulation  rate  calculated  from  CO2 


was  -—  =  7.9  liters  per  minute.  As  the  venous  oxygen  pressure 

was  44.5  mm.  and  this  corresponds,  calculating  from  Figure  28, 
to  73  per  cent  saturation  of  the  haemoglobin,  the  blood  had  lost 
about  22  per  cent  of  its  combined  oxygen.  Adding  the  correspond- 
ing small  amount  of  dissolved  oxygen  this  corresponds  to  a  loss 
of  about  4.3  volumes  per  cent  of  oxygen.  Hence  the  circulation 

rate,   calculating  from  the  oxygen,  was  —  -  =   8.8  liters  per 

43 
minute. 

No.  2.  27/2/1$.  Bar.  752  mm. 

Mixture  used  contained  6.26  per  cent  of  CO2  and  5.26  per  cent  of 

oxygen. 
First  alveolar  sample  2"  after  last  deep  inspiration,  CO2  =  6.26 

per  cent  and  O2  =  6.25  per  cent. 
Second  alveolar  sample  5"  after  first  sample,  CO2  =  6.30,  O2  = 

6.09  per  cent. 
Therefore  venous  CO2  pressure  =  6.30  per  cent  =  44.4  mm.  ;  and 

oxygen  pressure  6.09  per  cent  =  42.9  mm. 

Normal  alveolar  CO2  pressure  (mean)  =  5.55  per  cent  =  39.1  mm. 
Metabolism  332  cc.  of  CO2  and  374  cc.  of  oxygen  absorbed  (at  o° 

and  760  mm.)  per  minute. 

As  the  venous  CO2  pressure  was  5.3  mm.  above  the  arterial,  the 
blood  (calculating  from  Figure  26)  had  gained  3.7  volumes  per 
cent  of  CO2.  Hence  the  circulation  rate  calculated  from  CO2  was 

-  =  9.0  liters  per  minute.  As  the  venous  oxygen  pressure  was 
o  / 

42.9  mm.,  and  this  corresponds  (Figure  28)  to  70  per  cent  satura- 
tion of  the  haemoglobin,  the  blood  had  lost  about  25  per  cent  of 
combined  oxygen  or  about  4.9  volumes  per  cent  of  oxygen.  Hence 


the  circulation  rate,  calculating  from  the  oxygen,  was      —  =  g.o 

47 
liters  per  minute. 

If  we  take  these  two  experiments  together,  the  circulation  rate 
determined  from  the  CO2  was  8.45  liters  per  minute,  and  from 


268  RESPIRATION 

the  oxygen  8.40  liters,  the  general  mean  being  8.4  liters.  As  my 
pulse  rate  was  80  to  85  per  minute  this  means  that  just  about  100 
cc.  of  blood  were  delivered  at  each  heartbeat;  and  as  my  blood 
volume  is  about  4.8  liters  (see  p.  280  of  the  Pike's  Peak  Expedi- 
tion's Report)  a  volume  of  blood  equal  to  that  in  the  whole  body 
was  passing  round  every  35  seconds. 

This  is  a  much  higher  rate  than  has  usually  been  calculated  in 
recent  years,  but  not  higher  than  what  the  data  of  Loewy  and 
von  Schrotter  indicate.  There  are  so  many  sources  of  probable 
error  in  the  nitrous  oxide  method,7  that  I  do  not  think  that  much 
stress  can  be  laid  on  the  lower  estimates  which  this  method  has 
given  during  the  resting  condition.  Nevertheless  it  is  already 
evident  from  our  experiments  that  considerable  individual  dif- 
ferences exist  in  the  resting  circulation  rate  in  man;  and  it  is 
probable  that  under  abnormal  conditions  both  the  circulation 
rate  and  the  delivery  per  beat  vary  considerably  even  in  persons 
of  the  same  weight. 

At  different  times  we  have  found  very  little  difference  in  the 
resting  venous  gas  pressures  of  the  same  individual.  These  gas 
pressures  seem  to  be  not  much  less  steady  during  rest  under 
normal  conditions  than  the  arterial  gas  pressures.  It  is  very  dif- 
ferent, however,  during  exertion.  The  smallest  muscular  exertion 
raises  the  venous  CO2  pressure,  and  the  rise  is  far  more  than 
corresponds  to  the  comparatively  slight  rise  in  arterial  CO2  pres- 
sure as  measured  in  the  ordinary  way  in  the  alveolar  air.  Hence 
it  is  now  perfectly  certain  that  the  general  circulation  rate  does 
not  increase  in  anything  like  direct  proportion  to  increased  me- 
tabolism. Even  with  moderate  exertion  (about  a  third  the  maxi- 
mum possible)  on  a  Martin's  ergometer,  the  difference  between 
arterial  and  venous  CO2  pressure  became  about  two  and  one-half 
times  as  great  as  usual,  so  that  the  venous  blood  could  not  be  more 
than  about  45  per  cent  saturated  with  oxygen.  So  far  as  we  can 
calculate  there  is  sometimes  more  increase  in  circulation  than  can 
be  accounted  for  by  increased  pulse  rate ;  but  the  increase  is  seldom 

7  For  instance,  it  seems  very  probable  that  while  the  breath  is  held  in  perform- 
ing an  experiment  the  blood  flow  to  the  heart,  and  consequently  through  the  lungs, 
is  temporarily  diminished.  Krogh  and  Lindhard,  misled,  as  we  believe,  by  the 
imperfect  mixture  of  oxygen  in  the  alveolar  air  in  their  experiments,  estimated  that 
there  is  a  greatly  increased  absorption  of  oxygen,  and  a  corresponding  abnormal 
increase  in  circulation,  while  the  breath  is  held ;  and  their  results  are  corrected 
accordingly.  The  correction,  which  is  a  large  one,  does  not  seem  to  us  to  be  war- 
ranted, and  without  it  their  results  come  much  closer  to  ours.  This  is  especially 
true  for  Lindhard's  later  results. 


RESPIRATION  269 

great.   Roughly  speaking,  therefore,  our   results  confirm  those 
obtained  by  Henderson  on  the  dog. 

Henderson  and  Prince  have  determined  in  a  number  of  persons 
the  oxygen  consumption  per  beat  of  the  heart,  or  what  they  call 
for  brevity  "the  oxygen  pulse."8  This  value  is  obtained  by  simply 
dividing  the  oxygen  consumption  per  minute  by  the  pulse  rate. 
Figure  69  shows  graphically  a  fairly  typical  example  of  their 


g 


25  25oo 

20  2000 

15  '500 

JO  'Ooo 

5  500 


Pulse  60          70         &o         90          100         no         120         130         140         150         160 

Figure  69. 

Subject  Y.  H.,  Weight  75  kilos.  Haemoglobin  107.  In  this  diagram  the 
broken  line  expresses  the  oxygen  consumption  per  minute,  the  dotted  line  the 
CO2  elimination,  and  the  solid  line  the  oxygen  pulse.  During  the  short  periods 
of  vigorous  exertion  and  rapid  heart  rates,  the  CO2  elimination  was  increased 
to  a  greater  extent  than  the  oxygen  consumption,  the  respiratory  quotient  even 
rising  above  unity  in  some  cases,  and  indicating  an  excessive  blowing  off 
of  C02. 

results.  It  will  be  seen  that  with  low  oxygen  consumption  per 
minute  the  oxygen  consumption  per  beat  is  low,  but  increases 
rapidly  up  to  a  maximum  as  the  oxygen  consumption  per  minute 
increases  owing  to  muscular  exertion.  When,  however,  this  maxi- 
mum is  reached,  further  increase  of  the  oxygen  consumption  per 
minute  causes  no  increase  in  the  oxygen  consumption  per  beat. 
Interpreting  these  data  in  the  light  of  our  own  experiments  on 
man,  and  Henderson's  former  experiments  on  the  heart  of  the  dog, 
the  increased  oxygen  consumption  per  beat  is  not  due  to  any 
marked  extent  to  increased  output  of  blood  per  beat,  but  to  in- 
creased utilization  of  the  charge  of  oxygen  in  the  arterial  blood. 

8  Yandell  Henderson  and  Prince,  Amer.  Journ.  of  Physiol.,  XXXV,  p.  106,  1914. 


2;o  RESPIRATION 

When  this  increased  utilization  reaches  its  physiological  limit, 
further  increase  in  the  oxygen  consumption  per  minute  can  only 
be  obtained  by  increase  in  the  rate  of  heartbeat. 

The  mixed  venous  blood  returning  to  the  heart  comes  from 
various  parts  of  the  body;  but  during  muscular  exertion  a  very 
greatly  increased  proportion  must  come  from  the  muscles.  Now 
there  is  evidence  from  a  series  of  experiments  by  Leonard  Hill 
and  Nabarro  that  the  venous  blood  returning  from  the  muscles 
contains  even  during  rest  far  less  oxygen  and  more  CO2  than  at 
any  rate  the  venous  blood  returning  from  the  brain.9  Without 
obstructing  the  vessels  they  collected  venous  blood  returning  from 
muscles  through  the  deep  femoral  vein,  and  from  the  brain 
through  the  torcular  Herophili  in  the  dog.  The  following  table 
shows  the  average  of  about  eight  determinations  in  each  case. 


OXYGEN,  VOLUMES           Percentage 

PER  CENT 

loss  of 

[Muscle 
Rest  \ 

Artery 
I8.IO 

Vein 
5-12 

Difference 
—  12.98 

oxygen 
72 

[Brain 

16.81 

13.39 

—   3.42 

20 

Tonic  [Muscle 
fit   \ 

17-05 

3.30 

—13.75 

8l 

[Brain 

15-17 

10.22 

—  4-95 

32 

Clonic  ("Muscle 
fit     \ 

18.66 

6.03 

—  12.63 

69 

[Brain 

15.77 

11.46 

—  4.3i 

27 

It  will  be  seen  ( I )  that  during  rest  the  blood  lost  three  and  one- 
half  times  as  much  of  its  charge  of  oxygen  in  the  muscles  as  in 
the  brain;  (2)  that  during  the  intense  activity  of  a  tonic  or  clonic 
fit  (produced  by  absinthe)  the  percentage  loss  of  oxygen  by  the 
blood  was  only  slightly  increased  in  either  the  brain  or  the  muscles. 
The  animals  were  anaesthetized  with  morphia  or  chloroform,  so 
it  is  possible  that  the  circulation  was  less  active  than  in  normal 
animals;  but  the  difference  between  the  brain  circulation  and 
that  through  muscles  is  none  the  less  striking. 

In  the  light  of  these  experiments  we  can  see  what  is  presumably 
happening  as  regards  the  mixed  venous  blood  during  muscular 

9  Leonard  Hill  and  Nabarro,  Journ.  of  Physiol.,  XVIII,  p.  218,   1895. 


RESPIRATION  271 

activity.  The  chief  reason  why  the  oxygen  diminishes  and  CO2 
increases  so  strikingly  is  that  the  mixed  venous  blood  contains 
a  much  larger  proportion  of  blood  from  muscles,  and  that  this 
blood  is  very  poor  in  oxygen  whether  the  muscles  are  working  or 
not.  During  rest  the  mixed  venous  blood  will  contain  but  little 
blood  from  the  muscles,  and  a  large  proportion  from  the  brain 
and  probably  other  parts  which  furnish  venous  blood  relatively 
rich  in  oxygen.  As  indicated  by  the  size  of  its  arteries,  the  brain 
has  a  very  rich  blood  supply,  going  mainly  to  the  gray  matter. 
Its  normal  oxygen  pressure  is  evidently  very  high;  and  this 
renders  intelligible  the  fact  that  it  is  so  sensitive  to  deficient  satu- 
ration of  the  arterial  blood  with  oxygen.  The  rapid  circulation 
explains  the  promptness  of  its  reaction  to  changes  in  quality  of 
the  arterial  blood. 

The  fact  that  during  muscular  exertion  the  mixed  venous  blood 
contains  much  less  oxygen  and  more  CO2  explains  why,  if  the 
breath  is  voluntarily  held  during  exertion,  the  alveolar  CO2 
percentage  shoots  up  much  higher  than  if  it  is  held  for  a  far 
longer  time  during  rest.  It  also  explains  what  would  otherwise 
be  a  very  puzzling  fact  with  regard  to  congenital  heart  affections 
("morbus  coeruleus").  In  cases  of  morbus  coeruleus  the  face 
becomes  intensely  blue  on  muscular  exertion.  Quite  evidently  the 
arterial  blood  is  very  imperfectly  oxygenated ;  and  Douglas  and  I 
found  that  the  blueness  continues  even  if  the  patient  breathes  pure 
oxygen  during  the  exertion.  The  blueness  is  due  to  part  of  the 
venous  blood  short-circuiting  through  a  congenital  direct  com- 
munication between  the  right  and  left  sides  of  the  heart,  so  that 
the  mixed  arterial  blood  always  contains  a  certain  proportion  of 
unae' rated  venous  blood.  During  rest  this  venous  blood  contains 
so  much  oxygen  that  the  cyanosis  is  only  slight ;  but  during  exer- 
tion, with  much  less  oxygen  in  the  venous  blood,  the  cyanosis  is  of 
course  far  more  marked,  and  the  breathing  of  oxygen  avails  very 
little  towards  redressing  the  balance. 

It  is  evident  from  the  facts  just  referred  to  that  the  increase  in 
blood  flow  through  the  lungs  during  exertion  is  very  much  less 
than  the  increase  in  air  breathed.  At  first  sight,  therefore,  it  might 
seem  that  the  regulation  of  circulation  differs  fundamentally  from 
the  regulation  of  breathing.  A  little  consideration,  however,  shows 
that  there  are  no  real  grounds  for  this  conclusion.  If  we  take  as  our 
measure,  not  the  blood  flow  through  the  heart,  but  the  blood  flow 
through  individual  parts  of  the  body,  the  facts  so  far  discussed  do 
not  point  to  any  other  conclusion  than  that  the  blood  flow,  just 


272  RESPIRATION 

like  the  breathing,  is  delicately  regulated  in  accordance  with  the 
local  requirements  for  the  supply  of  oxygen  and  removal  of  CO2. 

The  idea  that  the  local  circulation  is  regulated  in  accordance 
with  the  local  CO2  pressure  was  brought  forward  in  a  very  definite 
form  by  Yandell  Henderson  in  a  series  of  papers  on  "Acapnia  and 
Shock."10  He  showed,  firstly,  that  the  local  circulation  and  func- 
tional activity  in  the  exposed  intestines  depends  upon  the  main- 
tenance in  them  of  a  sufficient  pressure  of  CO2,  and  secondly,  that 
on  the  removal  of  an  excessive  quantity  of  CO2  from  the  body  by 
excessive  artificial  or  natural  respiration  the  circulation  fails, 
whereas  excessive  ventilation  with  air  to  which  sufficient  CO2  has 
been  added  produces  no  such  effect.  These  are  evidently  facts  of 
fundamental  importance  as  regards  the  regulation  of  the  circula- 
tion, and  as  showing  the  intimate  connections  between  respiration 
and  circulation.  On  these  and  other  observations  he  also  based  the 
theory  that  the  immediate  cause  of  shock  may  be  excessive  res- 
piratory activity. 

The  blood-gas  changes  caused  by  excessive  artificial  respira- 
tion were  first  investigated  by  Ewald  in  connection  with  apnoea.11 
He  not  only  found  that  there  is  a  slight  excess  of  oxygen  and  very 
large  deficiency  of  CO2  in  the  arterial  blood,  but  also  (though  of 
this  he  did  not  realize  the  significance)  that  there  is  great  de- 
ficiency of  both  CO2  and  oxygen  in  the  mixed  venous  blood.  The 
changes  in  the  arterial  blood  have  already  been  discussed  in  earlier 
chapters,  and  it  was  pointed  out  in  Chapter  VII  that  owing  to  the 
deficiency  of  CO2  a  state  of  anoxaemia  must,  other  things  being 
equal,  be  produced  by  forced  breathing.  Ewald's  analyses  show, 
however,  that  there  is  something  more  to  cause  anoxaemia  than 
mere  deficiency  of  CO2.  The  latter  would  not  by  itself  account 
for  the  deficiency  of  oxygen  combined  with  haemoglobin  in  the 
venous  blood.  In  long  experiments  Ewald  found  this  oxygen  down 
to  about  a  third  of  the  normal,  and  the  CO2  down  to  half  the 
normal.  Taking  into  account  both  the  direct  effect  of  deficiency 
of  CO2  in  diminishing  the  free  oxygen  present  in  the  venous  blood, 
and  the  effect  in  the  same  direction  of  the  diminished  proportion 
of  oxyhaemoglobin  present,  the  artificial  respiration  must  have 
brought  about  a  condition  of  very  intense  anoxaemia  in  the  tis- 
sues. But  the  diminution  in  the  proportion  of  oxyhaemoglobin 

10  Yandell  Henderson,  Amer.  Journ.  of  Physiol.,  XXI,  p.  126,  1908;  XXIII, 
p.  345,  1909;  XXIV,  p.  66,  1909;  XXV,  p.  310,  1910;  XXV,  p.  385,  1910; 
XXVI,  p.  260,  1910;  XXVII,  p.  152,  1910;  XLVI,  p.  533,  1918. 

"Ewald,  Pfluger's  Archiv.,  VII,  p.  575,   1873. 


RESPIRATION  273 

cannot  have  been  due  to  any  other  cause  than  diminution  in  the 
circulation  rate;  and  this  diminution  is  shown  far  more  directly 
by  Yandell  Henderson's  experiments  and  numerous  blood-gas 
analyses  by  the  ferricyanide  method.  The  diminution  in  circula- 
tion goes  so  far  that  the  venous  return  to  the  heart  becomes  quite 
inadequate  to  fill  the  ventricles.  Hence  arterial  as  well  as  venous 
pressure  finally  falls,  and  the  heart  itself  is  inadequately  supplied 
with  free  oxygen  or  CO2,  and  gradually  fails  along  with  fail- 
ure in  the  brain  and  other  parts  of  the  body. 

Slowing  of  the  circulation  through  the  hands  during  forced 
breathing  was  clearly  demonstrated  by  his  calorimetric  method  by 
G.  N.  Stewart.11A 

By  means  of  the  new  method  for  determining  venous  gas  pres- 
sures in  man  we  found  that  though  there  is  a  considerable  fall, 
after  forced  breathing  for  about  three  minutes,  in  the  CO2  con- 
tent of  the  mixed  venous  blood,  there  is,  relatively  speaking,  an 
even  greater  fall  in  the  oxygen  content.  The  experiments  were 
difficult  because  of  the  mental  state  of  the  subject.  I  had  to  be 
watched  very  closely  to  see  that  I  carried  out  the  proper  manipula- 
tions, and  many  experiments  failed  because  of  gross  errors,  such 
as  taking  in  a  deep  breath  of  ordinary  air  from  the  room.  The  gas 
mixture  used  had  to  contain  less  than  4  per  cent  of  oxygen  and 
less  than  5  per  cent  of  CO2.  The  fall  in  oxygen  pressure  was  con- 
siderably more  than  could  be  accounted  for  as  due  to  the  fall  in 
CO2  pressure  on  account  of  the  Bohr  effect.  Hence  the  circulation 
rate  was  diminished.  The  mental  condition  was  apparently  due  to 
marked  anoxaemia  of  the  nervous  centers ;  and  it  may  be  remarked 
that  owing  to  the  rapid  normal  circulation  through  the  brain  the 
effects  of  the  forced  breathing  must  be  felt  there  sooner  than  else- 
where. 

We  also  investigated  the  effect  on  the  circulation  of  a  moderate 
excess  of  CO2,  sufficient  to  increase  the  breathing  to  about  five 
times  the  normal.  This  was  easily  accomplished  in  a  respiration 
chamber  in  which  the  CO2  percentage  had  been  raised  to  a  little 
over  5  per  cent.  Under  this  condition  there  was  a  slight  rise  in 
both  my  arterial  and  venous  CO2  pressure;  but  the  difference 
between  them  was  not  diminished.  Thus  there  had  been  no  ap- 
preciable increase  in  the  circulation  rate.  It  was  quite  clear  that 
the  circulation  does  not  increase  with  increased  arterial  CO2  pres- 
sure in  a  manner  corresponding  to  the  increase  of  breathing.  The 

UAG.  N.  Stewart,  Amer.  Journ.  of  Physiol.,  XXVIII,  p.  190,  1911. 


274  RESPIRATION 

breathing  had  increased  five  times  or  more,  but  the  circulation 
had  apparently  not  increased  at  all.  The  pulse,  etc.,  were  also 
hardly  affected.  With  a  great  excess  of  CO2,  however,  the  ve- 
nous return  to  the  right  heart  is  evidently  much  increased.  This 
was  first  definitely  observed  by  Yandell  Henderson,  who  also 
makes  the,  to  me,  interesting  remark  that  he  first  noted  the  signs 
of  increased  circulation  rate  on  myself,  while  I  was  nearly  over- 
come by  accumulation  of  CO2  in  a  mine- rescue  apparatus,  without 
any  deficiency  of  oxygen.12  Similarly,  great  deficiency  of  CO2,  as 
in  forced  breathing  or  excessive  artificial  respiration,  will  dim- 
inish the  circulation  rate;  and  it  seemed  probable  that  great  in- 
crease in  the  oxygen  pressure  in  the  tissues  (though  this  is  difficult 
to  produce  except  under  the  high  atmospheric  pressures  referred 
to  in  Chapter  XII)  would  have  a  similar  effect. 

That  this  effect  is  actually  produced  in  man  is  indicated  by  the 
results  of  quite  recent  experiments  by  Dautrebande  and  myself.13 
We  found  that  when  pure  oxygen  was  breathed,  particularly  under 
a  barometric  pressure  increased  to  two  atmospheres,  the  breathing 
increases,  as  shown  by  a  fall  in  alveolar  CO2  pressure,  and  there 
is  a  simultaneous  slowing  of  the  pulse.  This  indicated  a  slowing 
of  circulation  through  the  brain,  such  as  would  compensate  for 
the  high  oxygen  pressure  of  the  arterial  blood.  The  slowing  would 
of  course  raise  the  pressure  of  CO2  in  the  brain,  and  thus  increase 
the  breathing.  It  would  also  explain  the  fact  that  though  oxygen 
at  two  atmospheres  pressure  has  a  rapid  poisonous  action  on  the 
lungs  and  other  living  tissues  directly  exposed  to  it  (see  Chapter 
XII),  there  are  no  evident  cerebral  symptoms  until  oxygen  at 
much  higher  pressures  is  breathed. 

The  responses  involved  in  the  chemical  control  of  the  venous 
return  to  the  right  heart  were  found  by  Henderson  and  Harvey  to 
be  peripheral,  but  independent  of  the  vasomotor  nerves  and  nerve 
endings.  In  the  "spinal"  cat  they  found  that  slow  injections  of 
adrenalin,  and  other  prolonged  vasomotor  stimulations,  cause  a 
maintained  elevation  of  arterial  pressure,  but  only  an  evanescent 
rise  of  venous  pressure.  Ventilating  the  lungs  with  air  rich  in  CO2 
(with  ample  oxygen)  has,  on  the  contrary,  in  the  absence  of  the 
medullary  vasomotor  center,  no  appreciable  direct  effect  upon 
arterial  pressure,  but  induces  a  gradual,  sustained  and  large  eleva- 
tion of  venous  pressure.  They  note  also  that  during  this  action 

"Yandell  Henderson  and  Harvey,  Amer.  Journ.  of  PAysiol.,  XLVI,  p.  533, 
1918. 

18  Dautrebande  and  Haldane,  Journ.  of  Physiol.,  LV,  p.  296,  1921. 


RESPIRATION  275 

the  veins  are  always  relaxed,  as  well  as  distended ;  and  they  con- 
sider that  the  easier  escape  of  the  blood  from  the  tissues,  due  to 
relaxation  especially  of  venules,  is  the  cause  of  the  larger  venous 
return  and  consequent  rise  of  venous  pressure.  Recently  Hender- 
son, Haggard,  and  Coburn14  have  shown  that  inhalation  of  air 
containing  6  or  8  per  cent  of  CO2  has  a  powerful  restorative  effect 
upon  the  circulation,  and  particularly  upon  the  venous  pressure, 
in  patients  after  prolonged  anaesthesia  and  major  surgical  opera- 
tions. 

With  great  deficiency  of  oxygen  there  is  also  at  first  a  very 
marked  increase  in  the  circulation  rate.  This  is  shown  by  the 
greatly  increased  pulse  rate,  deep  blue  flushing  of  the  skin,  etc., 
and  great  rise  of  venous  blood  pressure  when  air  very  deficient  in 
oxygen  is  breathed.  In  rapid  poisoning  by  CO  there  is  the  same 
flushing  of  the  skin  and  distention  of  large  veins,  though  the  color 
is  now  red  and  not  blue.  The  increased  pressure  in  the  great  veins 
causes  the  distention  of  the  right  side  of  the  heart  and  rapid  pro- 
duction of  oedema  of  the  lungs  so  characteristic  of  acute  asphyxia, 
although  but  for  the  fact  that  the  heart  muscle  is  lamed  by  the 
anoxaemia  there  would  probably  be  no  over-distention.  As  Star- 
ling and  Knowlton  found,  oedema  of  the  lungs  and  over-disten- 
tion of  the  right  side  of  the  heart  are  very  quickly  produced  by  a 
quite  moderate  increase  of  the  ordinary  very  low  venous  pressure 
at  the  entry  to  the  heart.15  With  moderate  oxygen  deficiency,  pro- 
duced rapidly,  there  are,  just  at  first,  distinct  signs  of  increased 
circulation  as  well  as  of  increased  respiration;  but  very  soon  the 
increased  washing  out  of  CO2  from  the  blood  moderates  both  the 
breathing  and  circulation,  and  after  a  short  time  the  circulation, 
as  well  as  the  breathing,  quiets  down,  so  that  unless  the  anoxaemia 
is  considerable  the  increased  pulse  rate  and  other  signs  of  in- 
creased circulation  may  have  practically  disappeared. 

The  circulation  during  and  just  after  forced  breathing  in  man 
was  meanwhile  investigated  by  a  quite  different  method  by  Hen- 
derson, Prince,  and  Haggard.16  They  measured  the  venous  pres- 
sure by  observing  the  height  of  the  column  of  blood  in  a  vein  of 
the  arm  when  the  subject  was  placed  in  a  head  down  position  on  a 
sloping  board  (Figure  70) ,  thus  obtaining  a  measure  of  the  venous 

14  Henderson,  Haggard,  and  Coburn,  Journ.  Amer.  Med.  Assn.,  LXXIV,  p.  783, 
1920. 

15  Starling  and  Knowlton,  Journ.  of  Physwl.,  XLIV,  p.  206,  1914. 

18  Yandell  Henderson,  Prince,  and  Haggard,  Journ.  of  Pharmac.  and,  Exper. 
Therapeutics,  XI,  p.  203,  1918. 


276 


RESPIRATION 


blood  pressure  at  the  entry  to  the  heart.  The  effect  of  forced 
breathing  was  to  cause  a  great  diminution  in  venous  blood  pres- 
sure. Thus  the  supply  of  blood  to  the  heart  must  have  become 
inadequate  to  fill  the  right  ventricle.  Owing,  however,  to  the 
diminished  outflow  of  blood  from  the  arterial  system  there  was 
no  fall  in  arterial  blood  pressure.  It  seems  to  be  only  when  the 
anoxaemia  of  forced  breathing  becomes  so  intense  as  to  affect  the 
heart  muscle  seriously  that  the  arterial  blood  pressure  falls. 


Figure  70. 

Measurement  of  venous  blood  pressure  by  placing  subject  in  a  head-down 
position. 

Putting  all  these  facts  together,  it  appears  that  in  general  the 
circulation  is  so  regulated  as  to  keep  the  pressures  of  both  oxygen 
and  CO2  approximately  steady  in  the  venous  blood  from  any 
particular  organ.  The  regulation  is  evidently  of  a  double  kind, 
involving  both  oxygen  and  CO2.  If  the  oxygen  pressure  goes 
down  and  the  CO2  pressure  also  goes  down,  as  in  a  pure  anox- 
aemia, there  is  comparatively  little  effect  on  the  circulation  rate, 
because  increase  due  to  the  lowered  oxygen  pressure  is  at  once 
counteracted  by  the  effect  of  diminution  due  to  the  lowered  CO2 
pressure.  Similarly,  in  an  atmosphere  containing  simple  excess  of 
CO2  increased  circulation  due  to  the  excess  of  CO2  pressure  tends 
to  be  counteracted  by  decrease  due  to  increased  oxygen  pressure. 
During  muscular  work,  on  the  other  hand,  there  is  both  a  rise  of 
CO2  pressure  and  fall  of  oxygen  pressure,  and  consequently  a 


RESPIRATION  277 

great  increase  in  blood  flow  through  the  muscles,  with  a  corre- 
sponding increase  in  venous  blood  pressure,  as  Henderson  and 
his  colleagues  found  with  the  apparatus  shown  in  Figure  7O.17 

The  correspondence  between  blood  flow  and  amount  of  work 
done  by  a  muscle  seems  to  appear  clearly  in  data  obtained  by 
Markwalder  and  Starling  for  the  coronary  circulation  with  vary- 
ing work  of  the  heart  in  a  heart-lung  preparation.17A  The  amount 
of  blood  pumped  by  the  heart,  the  aortic  blood  pressure,  and  the 
flow  through  the  coronary  vessels,  were  measured  simultaneously. 
The  data  show  that  if  the  work  done  is  estimated  by  the  amount 
of  blood  pumped  multiplied  by  the  aortic  pressure,  the  coronary 
blood  flow  varied  within  wide  limits  in  proportion  to  the  work 
done.  The  variations  in  coronary  blood  flow  might,  of  course,  be 
attributed  to  the  variations  in  aortic  blood  pressure,  but  this  inter- 
pretation does  not  seem  to  explain  more  than  a  small  part  of  the 
facts. 

At  first  sight  the  regulation  of  the  circulation  appears  to  be 
different  from  that  of  respiration,  since  in  the  case  of  the  latter 
the  influence  of  CO2  predominates.  This,  however,  is  simply  be- 
cause when  ordinary  air  is  breathed  the  oxygen  pressure  in  the 
tissues  is  not  increased  when  the  breathing  increases.  In  reality, 
there  is  no  fundamental  difference.  Whenever  anoxaemia  is  pres- 
ent the  respiratory  regulation,  as  already  shown  in  Chapter  VII, 
works  just  like  the  local  circulatory  regulation.  The  breathing  is 
not  then  free  to  increase  in  such  a  way  as  to  compensate  approxi- 
mately for  increasing  anoxaemia,  because  increased  breathing 
lowers  the  CO2  pressure  and  this  tends  to  diminish  the  breathing. 
Similarly  the  breathing  cannot  increase  freely  with  increased 
CO2  pressure,  because  the  increased  breathing  would  diminish 
the  anoxaemia.  Under  deep  anaesthesia,  when  the  arterial  blood 
becomes  dark,  CO2  has  very  little  effect  on  the  breathing. 

There  can  be  little  doubt  that  in  the  case  of  circulation,  just  as 
in  that  of  respiration,  increase  in  CO2  pressure  stands  simply  for 
increase  in  hydrogen  ion  concentration.  Hence  alkalosis  due  to 
deficiency  of  CO2  in  the  systemic  capillaries,  or  acidosis  due  to 
excess,  will  tend  to  be  relieved  by  the  slow  acclimatization  changes 
described  in  Chapter  VIII. 

When  once  the  fundamental  fact  is  grasped  that  the  general 
flow  of  blood  throughout  the  body  is  correlated  with  the  gas  pres- 

17  Yandell  Henderson  and  Haggard,  Journ.  of  Pharmac.  and,  Exper.  Therap.t 
XI,  p.  197,  1918. 

17A  Markwalder  and  Starling,  Journ.  of  Physiol.,  XLVII,  p.  279,  1913. 


278  RESPIRATION 

sures  in  the  capillaries,  the  whole  physiology  of  the  circulation 
appears  in  a  new  light.  It  is  not  the  heart  nor  the  bulbar  nervous 
centers  which  govern  the  circulation  rate,  but  the  tissues  as  a 
whole;  and  they  govern  it  with  an  accuracy  and  delicacy  com- 
parable to  the  accuracy  and  delicacy  with  which  they  govern 
breathing.  The  heart  and  vaso-motor  system  are  only  the  executive 
agents  which  carry  out  the  bidding  of  the  tissues,  just  as  the  lungs 
and  nervous  system  do  in  the  case  of  breathing. 

It  appears  that  the  immediate  function  of  the  heart  is  not  to 
regulate  the  circulation  rate,  but  simply  to  pass  on  at  a  greatly 
increased  pressure  the  blood  supplied  to  it.  The  problem  of  the 
regulation  of  the  circulation  under  normal  conditions  seems  in  the 
main  to  resolve  itself  into  that  of  the  regulation  by  the  tissues  of 
the  amount  of  blood  supplied  to  the  heart;  and  this  regulation 
depends,  as  we  have  just  seen,  to  an  overwhelming  extent  on  a 
linked  control  by  the  oxygen  pressure  and  hydrogen  ion  concen- 
tration in  the  systemic  capillaries. 

Just  as  in  the  case  of  regulation  of  breathing,  so  also  in  the 
case  of  regulation  of  the  circulation,  the  dominant  facts  have  been, 
and  still  are,  obscured  by  masses  of  detail  which,  in  their  un- 
connected form,  simply  confuse  the  mind  and  lead  to  wholly 
mistaken  judgments.  It  is  difficult  to  pick  a  way  through  all  these 
details,  but  the  salient  points  concerning  the  immediate  control  of 
the  heart's  action  must  now  be  referred  to. 

We  owe  mainly  to  Gaskell  the  demonstration  that  the  muscular 
fibers  of  the  heart  may  continue  to  contract  rhythmically  apart 
from  nervous  control  and  even  when  they  are  separated  from  one 
another,  just  as  the  rhythmic  activity  of  the  respiratory  center 
continues  apart  from  peripheral  nervous  control.  When,  however, 
different  parts  of  the  heart  are  separated  from  one  another,  the 
frequency  of  the  contractions  in  the  different  parts  is  different, 
the  ventricular  contracting  less  frequently  than  the  auricular 
parts.  In  lower  vertebrates  the  order  of  frequency  in  contractions 
is  sinus  venosus,  auricle,  ventricle,  and  bulbus  arteriosus.  More- 
over the  individual  fibers  in  each  separated  part  contract  normally 
in  unison  with  one  another  so  long  as  they  are  not  separated.  In  a 
normal  intact  heart,  however,  not  only  do  the  individual  fibers  in 
sinus  venosus,  auricles,  ventricles,  and  bulbus  arteriosus  contract 
in  unison,  but  so  also  do  all  the  parts  of  the  heart. 

The  explanation  of  this  contraction  in  unison  has  been  furnished 
by  the  physiological  and  clinical  investigations  of  the  last  few 
years.  As  was  shown  by  Lewis  with  the  help  of  the  string  gal- 


RESPIRATION  279 

vanometer,  each  normal  contraction  starts  in  what  is  known  as 
the  Keith-Flack  node,  an  island  of  primitive  sinus  venosus  tissue 
in  the  right  auricle.  Thence  it  is  conducted  by  primitive  muscular 
tissue  to  the  auricles,  and  by  a  bundle  of  similar  muscular  tissue, 
the  bundle  of  Kent  or  His,  to  the  ventricles.  This  primitive  tissue 
is  distributed  (as  the  fibers  of  Purkinje)  over  the  ventricles,  and 
has  a  conduction  rate  far  faster  than  the  rest  of  the  muscular  tis- 
sue of  the  heart.  Thus  all  parts  of  the  ventricles  contract  almost 
simultaneously,  and  shortly  after  the  almost  simultaneous  con- 
traction of  all  parts  of  the  auricles;  while  the  pace  of  the  whole 
heart  is  set  by  the  contractions  starting  in  the  Keith-Flack  node. 
Impairment  or  total  failure  in  the  conduction  from  auricle  to 
ventricle,  or  from  fiber  to  fiber  in  auricle  or  ventricle,  explains 
many  of  the  peculiarities  met  with  in  heart  affections. 

So  long  as  the  contractions  of  the  ventricles  are  complete,  the 
volume  of  blood  discharged  at  each  beat  must  depend  on  the  ex- 
tent to  which  the  right  ventricle  fills  in  diastole.  This,  in  turn, 
depends  on  the  rate  at  which  blood  is  let  through  from  the  arteries 
to  the  veins.  The  difference  between  arterial  and  venous  pressure 
is  so  great  that  accessory  factors  such  as  the  pumping  movements 
of  respiration  can  hardly  have  more  than  a  very  minute  average 
influence  on  the  circulation,  though  they  have  a  marked  tempo- 
rary influence.  It  is  therefore  the  rate  at  which  the  systemic 
blood  is  allowed  to  pass  through  the  tissues  into  the  venous  system 
that  determines  the  amount  of  blood  pumped  by  the  heart;  and, 
as  already  pointed  out,  the  rate  at  which  blood  is  allowed  to  pass 
through  the  tissues  is  determined  by  their  metabolic  requirements, 
and  particularly  by  the  amount  of  blood  required  to  keep  the 
diffusion  pressures  in  them  of  oxygen  and  carbonic  acid  approxi- 
mately steady. 

It  is  evident  that  in  the  carrying  out  of  this  regulation,  both  by 
the  heart  and  the  blood  vessels,  the  nervous  system  plays  a  very 
important  part,  just  as  in  the  case  of  regulation  of  breathing;  but 
the  main  fact  must  never  be  lost  sight  of  that  the  primary  factor 
in  determining  the  rate  of  circulation  is  neither  the  heart  nor  the 
nervous  centers  specially  connected  with  the  circulation,  but  the 
metabolic  activities  of  the  tissues.  At  bottom  the  regulation  of  the 
circulation  is  a  chemical  regulation,  just  as  in  the  case  of  the 
breathing. 

The  frequency  and  strength  of  the  heartbeats  are  moderated 
through  the  central  nervous  system,  first  by  the  well-known  in- 
hibitory impulses  passing  to  the  heart  through  the  vagus  nerve, 


28o  RESPIRATION 

and  secondly  by  the  equally  well-known  accelerator  impulses 
passing  to  the  heart  through  sympathetic  branches.  Increased 
liberation  of  inhibitory  impulses  has  been  found  to  be  a  direct  re- 
sult of  rise  of  arterial  blood  pressure  (so  that  the  inhibition  tends  to 
prevent  an  excessive  rise  of  arterial  pressure  and  consequent  fa- 
tigue of  the  heart  or  over-distention  of  arteries),  but  is  certainly 
also  a  result  of  rise  in  oxygen  pressure  and  diminution  in  CO2 
pressure  in  the  blood  passing  through  the  brain.  An  increase  of 
arterial  blood  pressure  will,  therefore,  owing  to  the  increased 
rate  of  circulation,  slow  the  heart.  When  the  arterial  blood  pres- 
sure is  normal  there  is  a  considerable  amount  of  vagus  inhibition, 
so  that  on  section  of  the  vagi  the  heartbeats  quicken.  It  appears 
also  that  this  tonic  nervous  inhibition  of  the  heart  is  itself  reflexly 
inhibited,  either  directly  or  indirectly,  by  increase  of  pressure  on 
the  great  veins  opening  into  the  heart.  This  was  recently  shown  by 
Bainbridge,18  who  found  that,  even  if  the  accelerator  nerves  are 
cut,  increase  in  venous  pressure  causes  marked  quickening  of  the 
heartbeats  provided  that  the  vagi  are  still  intact.  He  showed  that 
any  considerable  increase  in  venous  pressure  causes  quickening 
of  the  heartbeat,  and  that  the  quickening  depends  upon  the  in- 
tegrity of  the  vagus  nerves.  Part,  at  any  rate,  of  this  effect  is  due 
to  inhibition  of  the  tonic  inhibitory  action  of  efferent  vagus  fibers. 
Another  part  is  probably  due  to  reflex  excitation  of  accelerator 
nerves,  but  on  this  point  the  evidence  was  not  so  clear.  The  action 
of  the  heart  is  not  subject  to  direct  voluntary  control,  but  the  ef- 
fects of  emotional  stimuli  on  the  rate  of  heartbeat  are  well  known 
and  very  evident. 

There  is  no  necessary  connection  between  rate  of  heartbeat  and 
circulation  rate.  This  has  been  shown  by  various  experiments,  but 
most  strikingly  by  the  experiments  of  Starling  and  his  pupils  on 
the  bodies  of  animals  in  which  an  artificial  circulation  through 
the  heart  and  lungs  alone  had  been  established,  the  physiological 
connections  with  central  nervous  system  and  rest  of  the  body  being 
cut  off.  In  such  a  "heart-lung  preparation"  the  rate  of  heartbeat 
remains  steady  for  long  periods  if  the  temperature  is  kept  steady 
and  artificial  respiration  is  maintained;  but  the  flow  of  blood  can 
be  varied  within  very  wide  limits  by  simply  varying  the  rate  at 
which  blood  is  supplied  to  the  right  side  of  the  heart.  Thus  Pat- 
terson and  Starling  found  that  with  a  pulse  rate  which  was  steady 
at  144  the  circulation  rate  in  a  heart-lung  preparation  from  the 

18  Bainbridge,  Journ.  of  Physiol.,  L,  p.  65,  1915. 


RESPIRATION  281 

dog  could  be  varied  from  215  to  2,000  cc.  per  minute  by  simply 
regulating  the  supply  of  blood  to  the  right  side  of  the  heart.19 

The  heart  is  thus  a  pump  which  is  capable  of  adjusting  its  out- 
put without  any  variation  in  rate  of  stroke ;  and  we  might  imagine 
a  heart  working  quite  efficiently  on  this  principle,  without  any 
-regulation  by  the  nervous  system.  The  circulation  would  adjust 
itself  automatically  in  accordance  with  the  rate  at  which  blood 
was  allowed  to  pass  through  the  systemic  capillaries;  and  the 
resistance  in  the  arterioles  and  capillaries  would  automatically 
maintain  a  sufficient  arterial  blood  pressure. 

It  is  possible  that  in  certain  cases  of  heart  disease,  where  the 
physiological  connection  between  auricles  and  ventricles  through 
the  bundle  of  Kent  and  His  is  broken,  the  circulation  is  main- 
tained in  this  way,  since  in  these  cases  the  pulse  rate  does  not 
change  during  the  very  limited  amount  of  muscular  exertion 
which  is  possible.  In  normal  persons  or  animals,  however,  the 
pulse  rate  increases  very  markedly  during  muscular  exertion ;  and 
in  persons  in  whom,  owing  to  some  nervous  or  cardiac  abnormality 
this  increase  does  not  occur,  the  capacity  for  exertion  is  very  small. 
We  must  infer,  therefore,  that  under  normal  conditions  the  ca- 
pacity of  the  heart  for  increasing  the  circulation  rate  without 
increase  of  the  rate  of  heartbeat  is  very  limited — far  more  so  than 
might  be  inferred  from  study  of  a  heart-lung  preparation.  In 
other  words  the  output  of  the  heart  during  systole  is  usually 
pretty  constant  under  normal  conditions,  as  Henderson  was  the 
first  to  point  out. 

We  must  now  consider  in  more  detail  how  the  distribution  of 
blood  is  regulated.  It  has  been  known  since  the  discovery  by 
Claude  Bernard  of  vasomotor  nerves  that  the  distribution  of 
blood  in  the  body  is  regulated  through  the  nervous  system.  Vaso- 
constrictor nerves  are  known  to  be  widely  distributed  in  all  parts 
except  the  central  nervous  system,  and  vasodilator  nerves  have 
also  been  discovered  at  certain  points.  There  is  also  a  main  vaso- 
motor center  in  the  medulla  from  which  vasoconstrictor  impulses 
radiate,  and  subsidiary  vasomotor  centers  in  the  spinal  cord. 
Another  and  much  more  direct  means  of  regulating  the  distribu- 
tion of  blood  has  recently  been  discovered  by  Krogh.20  He  has 
found  by  microscopical  examination  of  living  capillaries,  and  by 
injection  of  Indian  ink,  that  under  resting  conditions  the  great 
majority  of  capillaries  in  muscular  and  other  tissues  are  firmly 

19  Patterson  and  Starling,  Journ.  of  PhysioL,  XLVIII,  p.  357,  1914. 

20  Krogh,  Journ.  of  Physiol.,  LII,  p.  457,  1919. 


282  RESPIRATION 

contracted  and  impermeable  to  blood,  so  that  neither  blood  cor- 
puscles nor  even  the  finest  particles  of  Indian  ink  can  pass 
through  them.  Nor  is  the  full  arterial  blood  pressure  capable  of 
forcing  them  open.  Whenever  the  tissue  is  stimulated  to  activity, 
however,  these  capillaries  open  wide,  so  that  blood  can  pass 
through  them  freely.  He  found,  for  instance,  that  in  muscle  of  the 
guinea  pig  about  twenty  times  as  many  capillaries  were  open 
during  activity  of  the  muscle  as  during  rest.  The  active  contrac- 
tility of  capillaries  had  been  directly  observed  by  Roy  and  Gra- 
ham Brown  in  1880,  but  the  real  significance  of  this  observation 
had  not  been  realized. 

Krogh's  observations  have  thrown  a  flood  of  new  light  on  the 
exchange  of  gases  and  other  material  between  the  blood  and  the 
living  tissues :  for  the  opening  out  of  new  capillary  paths  when- 
ever a  greater  exchange  of  material  is  taking  place  must  facili- 
tate enormously  the  exchange,  and  thus  furnish  a  means  of  keep- 
ing the  gas  pressures  in  the  tissues  approximately  normal  in  spite 
of  great  variations  in  metabolism.  During  muscular  work,  for 
instance,  the  immense  increase  of  capillary  paths  will  greatly 
facilitate  the  exchange  of  oxygen  and  carbonic  acid  between  the 
blood  and  the  muscle  fibers.  There  must  be  a  great  tendency  to 
fall  in  the  oxygen  pressure  of  the  blood  passing  through  the 
muscle  capillaries  during  muscular  work.  Unless  this  fall  were 
approximately  compensated  for  by  the  opening  out  of  new  capil- 
laries, it  is  difficult  to  see  how  a  sufficient  oxygen  supply  could  be 
maintained,  as  in  all  probability  the  oxygen  consumption  in  a 
muscle  during  very  hard  work  is  twenty  or  thirty  times  as  great 
as  during  rest.  We  can  also  now  understand  much  better  how  it 
comes  about,  for  instance,  that  when  the  skin  circulation  is  cut 
down  to  the  utmost  by  vasoconstriction  in  the  prevention  of  un- 
necessary loss  of  heat  from  the  body,  the  skin,  though  more  or 
less  blue  from  greatly  diminished  blood  flow,  may  be  still  full  of 
blood,  as  shown  by  the  full  blue  color. 

Probably  it  is  the  stimulus  of  the  presence  in  excess  of  certain 
metabolic  products,  particularly  carbonic  acid,  and  the  deficiency 
of  others,  particularly  oxygen,  that  determines  the  relaxation  of 
the  capillary  walls.  There  can  also  be  little  doubt  that  the  same 
stimuli,  acting  reflexly,  determine  the  activity  of  local  vasomotor 
nerves.  Temperature  stimuli,  or  irritation  stimuli,  appear  to  act 
in  a  similar  manner.  Stimuli  may  also  act  centrally,  however,  as 
in  the  general  regulation  of  body  temperature  by  variations  in  the 
skin  circulation,  or  in  emotional  vasomotor  changes. 


RESPIRATION  283 

How  very  powerfully  a  local  stimulus  may  act  on  local  blood 
circulation  is  strikingly  shown  by  a  recent  experiment  of  Meakins 
and  Davies.20A  They  found  that  when  the  arm  was  immersed  in 
cold  water  the  returning  venous  blood  was  completely  deprived 
of  oxygen.  On  the  other  hand,  when  the  arm  was  kept  in  hot  water 
the  haemoglobin  of  the  venous  blood  was  94  per  cent  saturated 
with  oxygen,  as  compared  with  96  per  cent  for  the  arterial  blood. 
The  oxygen  consumption  was  doubtless  much  greater  in  the  warm 
than  in  the  cold  skin,  so  the  difference  in  circulation  rate  must  have 
been  enormous. 

If  the  regulation  of  blood  distribution  in  the  body  were  simply 
a  matter  of  opening  the  proper  sluice  gates  according  to  local  re- 
quirements, the  matter  would  be  much  more  simple  than  it  is. 
Actually,  however,  the  contraction  and  dilatation  of  various  ar- 
teries, veins,  and  capillary  tracts  must  tend  to  have  the  effect  of 
varying  the  total  capacity  of  the  blood  vessels,  with  the  result  that 
the  venous  blood  pressure  at  the  heart  inlet  varies,  and  either  too 
little,  or  too  much,  blood  is  supplied  to  the  heart.  As  a  conse- 
quence, the  arterial  blood  pressure  would  either  tend  to  fall  too 
much  to  secure  an  adequate  supply  of  blood  to  the  brain  and  other 
parts,  or  else  to  rise  too  high. 

There  appears  to  be  an  elaborate  nervous  defense  against  such 
disturbances.  Excessive  rise  of  arterial  blood  pressure  is  guarded 
against,  not  only  by  the  reflex  vagus  inhibition  already  referred 
to,  but  also  by  reflex  vasomotor  inhibition  through  the  "depres- 
sor" branch  from  the  cardiac  vagus.  Excitation  of  the  depressor 
fibers  causes  inhibition  of  the  vasomotor  center  in  the  medulla  and 
consequent  dilatation  of  arteries  and  probably  veins  in  the  splanch- 
nic and  other  areas.  Depressor  action  is  brought  about  (whether 
directly  or  indirectly)  by  excessive  arterial  blood  pressure,  so 
that  the  pressure  is  relieved.  Deficiency  in  arterial  and  venous 
pressure  is  guarded  against  by  an  opposite  "pressor"  action  re- 
sulting in  excitation  of  the  vasomotor  center  and  consequent  rise  in 
blood  pressure.  A  normal  stimulus  to  pressor  action  of  the  center 
is  quite  evidently  deficiency  of  oxygen  combined  with  excess  of 
carbonic  or  other  acids  in  the  blood  supplying  the  brain.  Thus  the 
arterial  and  venous  blood  pressures  rise  very  markedly  in  response 
to  deficiency  of  oxygen  combined  with  excess  of  carbonic  acid, 
whether  produced  by  deficient  aeration  of  the  blood  or  circulatory 
failure.  A  very  important  effect  of  this  rise  of  blood  pressure  is 

SOA  Meakins  and  Davies,  Journ.  of  Path,  and,  Bact.,  XXIII,  p.  460,  1920. 


284  RESPIRATION 

to  concentrate  the  available  blood  flow  towards  the  brain.  In  mus- 
cular exertion  there  is  also  a  rise  of  blood  pressure,  due  partly  to 
the  effect  on  the  vasomotor  center  of  excess  of  CO2  and  deficiency 
of  oxygen  in  the  arterial  blood,  but  perhaps  partly  also  to  a  gen- 
eral pressor  action  complementary  to  a  local  depressor  action  on 
the  arteries  and  veins  concerned  in  supplying  the  muscles  with 
blood. 

We  may  compare  the  action  of  the  bulbar  centers  controlling 
blood  pressure  and  heart  rate  with  that  of  the  respiratory  center 
in  its  linked  responses  to  direct  chemical  and  peripheral  nervous 
stimuli;  but  data  are  not  yet  available  for  carrying  the  com- 
parison into  detail. 

From  this  general  survey  of  the  experimental  evidence  relating 
to  the  regulation  of  the  circulation,  it  will  be  seen  that  the  deciding 
factor  in  determining  the  rate  of  circulation  ancl  local  distribution 
of  blood  flow  is  local  or  general  deficiency  or  excess  in  the  diffusion 
pressures  of  the  substances  which  enter  into  tissue  metabolism, 
and  particularly  deficiency  or  excess  in  the  diffusion  pressures  of 
oxygen  and  carbonic  acid.  Temperature  is  also  a  factor,  but  per- 
haps not  a  different  one,  since  the  diffusion  pressure  of  a  sub- 
stance varies  as  its  absolute  temperature. 

The  regulation  of  the  circulation  may  be  abnormal  in  various 
ways,  and  the  present  chapter  would  be  incomplete  without  some 
reference  to  this  subject.  The  abnormality  may  arise  from  disease 
or  congenital  defect  of  the  heart  or  from  operative  interference, 
but  is  very  commonly  due  to  disorder  of  the  nervous  regulation, 
whether  or  not  any  organic  defect  is  also  present.  Another  form 
of  abnormal  circulation  is  due  to  a  deficient  volume  of  blood,  or  to 
abnormality  in  its  composition.  In  all  these  cases  the  abnormal 
circulation  is  reflected  in  abnormal  breathing.  Owing  to  the  ab- 
sence of  adequate  clinical  or  experimental  investigations  it  is 
difficult  as  yet  to  deal  with  this  subject  in  a  satisfactory  manner, 
and  I  can  only  attempt  to  discuss  it  tentatively  in  the  light  of  what 
is  already  known. 

The  effect  may  first  be  considered  of  a  valvular  defect  which 
either  causes  narrowing  of  valvular  openings  (stenosis)  or  makes 
a  valve  incompetent  so  that  there  is  regurgitation.  The  effect  of 
this  is  that,  other  things  being  equal,  more  work  is  thrown  on  one 
or  another  part  of  the  heart.  If  this  extra  work  is  not  serious  it 
may  be  completely  met,  and  partly  by  a  true  hypertrophy  of  the 
muscular  substance  on  which  the  increased  work  is  thrown;  but 
if  the  extra  work  is  serious  the  action  of  the  heart  as  a  pump  will 


RESPIRATION  285 

be  limited,  so  that  the  increased  circulation  required  during  mus- 
cular exertion  cannot  be  produced.  The  arterial  blood  pressure 
will  therefore  fall  during  muscular  work  of  more  than  a  certain 
amount.  In  consequence  of  this  the  coronary  circulation  may  also 
be  impaired,  with  possibly  dangerous  consequences  under  the  ex- 
isting circumstances ;  and  there  will  be  faintness  along  with  hy- 
perpnoea,  owing  to  slowed  circulation  and  hence  diminished  oxy- 
gen pressure  and  increased  CO2  pressure  in  the  capillaries  of  the 
brain.  During  rest,  however,  or  such  muscular  exertion  as  is  pos- 
sible without  abnormal  symptoms,  the  circulation  will  be  carried 
on  in  a  normal  manner. 

The  alveolar  CO2  pressure  in  a  number  of  cases  of  valvular 
heart  disease  was  investigated  by  Miss  FitzGerald,  and  found  to  be 
normal  except  in  cases  confined  to  bed  with  serious  symptoms.21 
The  absence  of  any  fall  in  the  alveolar  CO2  pressure  constituted 
good  evidence  of  the  absence  of  any  impairment  of  the  circula- 
tion during  rest.  In  cases  with  serious  symptoms  even  during  rest 
there  was  a  marked  fall  in  the  alveolar  CO2  pressure.  This  is  also 
the  case  in  congenital  heart  affections,  when  the  alveolar  CO2 
pressure  may  be  as  low  as  20  mm.22 

We  can  see  what  is  happening  in  these  cases.  Owing  to  the  im- 
paired or  short-circuited  circulation  the  oxygen  pressure  in  the 
tissues  falls  and  the  CO2  pressure  tends  to  rise.  This,  however, 
increases  the  breathing,  and  so  prevents  the  rise  of  CO2  pressure 
by  abnormally  diminishing  the  CO2  pressure  of  the  arterial  blood 
leaving  the  lungs.  The  fall  in  oxygen  pressure  cannot,  however, 
be  prevented  in  this  way,  as  the  increased  breathing  will  not 
materially  increase  the  oxygen  in  the  arterial  blood.  Some  anox- 
aemia will  therefore  be  present,  and  will  probably  show  itself  by 
the  color  of  the  skin  and  lips,  as  well  as  by  more  frequent,  and 
possibly  shallower,  breathing,  and  other  symptoms  of  anoxaemia. 
The  alkalosis  produced  by  the  increased  breathing  due  to  anox- 
aemia will  gradually  be  compensated  for  by  increased  excretion 
of  alkali  and  diminished  formation  of  ammonia,  just  as  at  a  high 
altitude  (see  Chapter  VII)  ;  and  this  will  tend  to  diminish  the 
real  anoxaemia  though  without  diminishing  the  cyanosis.  Unless 
the  breathing  became  shallow  no  material  relief  could  be  looked 
for  owing  to  active  secretion  of  oxygen  inwards  by  the  lung  ep- 
ithelium, as  this  would  only  slightly  increase  the  oxygen  in  the 

21  FitzGerald,  Journ.  of  Pathol.  and  Bact.,  XIV,  p.  328. 

*  French,  Pembrey,  and  Ryffel,  Journ.  of  Physiol.,  XXIX,  Proc.  P&ysiol.  Soc., 
p.  ix,  1909. 


286  RESPIRATION 

arterial  blood;  but  some  relief  may  come  from  compensatory  in- 
crease in  the  percentage  of  haemoglobin  in  the  blood.  In  a  bad 
heart  case  the  heart  has  usually  broken  down  owing  to  either  some 
more  or  less  acute  infection  or  to  too  much  muscular  exertion; 
and  usually  the  main  question  is  whether,  and  to  what  extent,  the 
heart  will  recover  with  rest  and  the  passing  off  of  the  infection. 

In  many  heart  affections  the  defect  is  in  the  nervous  regulation 
of  the  heart,  either  without  or  with  a  valvular  defect.  The  ac- 
celerator, inhibitory,  depressor,  or  pressor  reflexes  may  be  acting 
excessively.  Cases  with  evident  defects  of  nervous  control  have 
been  very  common  during  the  war,  under  such  names  as  "soldier's 
heart,"  "disordered  action  of  the  heart,"  "neurasthenia,"  etc.  In 
the  commonest  form  of  this  defect  there  is  very  abnormal  increase 
in  pulse  rate  on  slight  exertion  or  emotional  and  other  stimuli ; 
and  accompanying  the  increase  there  is  pain  and  hyperalgesia  in 
the  areas  where  pain  is  usually  felt  in  heart  affections.  The  exag- 
gerated cardiac  reflexes  seem  to  be  similar  to  the  exaggerated 
Hering-Breuer  respiratory  reflex  in  the  same  cases,  and  to  be  due 
to  the  same  causes  (see  Chapter  III).  Reflexes  and  nervous  or 
emotional  responses  of  all  kinds  are  exaggerated  in  these  cases  of 
neurasthenia;  and  the  exaggeration  of  cardiac  reflexes  is  fre- 
quently only  one  symptom  of  a  condition  of  general  neurasthenia. 
The  pain  is  probably  only  an  expression  of  fatigue  produced  by 
the  over-frequent  heartbeats. 

A  similar  condition  is  very  commonly  present  as  an  accompani- 
ment of  valvular  defect;  and  the  associated  shallow  breathing 
may  cause  very  serious  secondary  anoxaemia  in  the  manner  al- 
ready described  in  Chapter  VII.  This  seems  to  be  the  explanation 
of  the  orthopnoea  and  Cheyne-Stokes  breathing  so  often  seen  in 
bad  heart  cases,  and  also  explains  the  marked  effects  of  oxygen 
inhalation  in  relieving  the  symptoms.  Continuous  inhalation  of 
air  enriched  with  oxygen  is  likely  to  prove  a  very  valuable  remedy 
in  promoting  recovery  where  failure  of  the  respiratory  center  is 
complicating  defects  of  circulation. 

A  very  interesting  investigation  demonstrating  a  relation  be- 
tween vascular  disturbances  in  the  lungs  and  the  Hering-Breuer 
reflex  has  recently  been  published  by  J.  S.  Dunn,22A  who  was 
working  at  the  time  in  conjunction  with  Barcroft.  He  produced 
multiple  embolism  of  pulmonary  arterioles  by  intra-venous  injec- 
tion of  starch  granules.  When  only  a  moderate  degree  of  embolism 
was  produced  (so  as  not  to  cause  immediate  death)  he  observed 

MA  Dunn,  Quart.  Journ.  of  Med.,  XIII,  p.  129,  1920. 


RESPIRATION  287 

an  extraordinary  increase  in  frequency  and  diminution  in  depth 
(to  half  or  even  a  fourth)  of  respiration.  At  the  same  time  the 
rate  of  circulation  (measured  by  a  very  perfect  blood-gas  method 
described  in  the  same  journal  by  Barcroft,  Boycott,  Dunn  and 
Peters)  was  not  diminished,  nor  was  the  venous  blood  pressure 
raised,  or  the  arterial  pressure  disturbed :  nor  was  there  appreci- 
able deficiency  of  oxygen  or  excess  of  CO2  in  the  arterial  blood. 
But  when  the  vagi  were  cut  the  respirations  slowed  down  and 
became  normally  deep  at  once.  It  appears,  therefore,  that  the 
Hering-Breuer  reflex  (Chapter  III)  was  enormously  exaggerated 
as  a  result  of  the  disturbed  pulmonary  circulation.  Just  at  first  the 
breathing  was  stopped,  which  suggests  that  the  respiratory  move- 
ments were  jammed  completely  by  the  exaggerated  reflex.  These 
experiments  throw  a  quite  new  light  on  the  intense  and  exhausting 
dyspnoea  caused  by  pulmonary  embolism,  and  also  in  cardiac  cases 
where  there  is  rapid  breathing  without  other  cause.  How  the  vagus 
nerve  endings  are  excited  is  not  yet  clear.  The  discovery  of  a  drug 
capable  of  controlling  their  action  would  evidently  be  an  important 
advance  in  therapeutics. 

In  defective  circulation  owing  to  loss  of  blood  the  primary 
cause  of  breakdown  appears  to  be  that,  in  spite  of  contraction  of 
arterioles  and  venules  owing  to  pressor  reaction  of  the  vasomotor 
center,  there  is  not  sufficient  blood  to  fill  the  large  veins  and  ade- 
quately supply  the  right  side  of  the  heart.  As  a  consequence  the 
arterial  blood  pressure  falls  and  the  circulation  slows  down,  with 
consequent  anoxaemia  acting  most  seriously  on  the  brain,  and 
affecting  the  breathing  in  the  manner  already  explained  in  con- 
nection with  valvular  affections  where  compensation  is  imperfect. 
The  natural  remedy  for  this  condition  would  appear  at  first  sight 
to  be  a  pressor  excitation  of  the  vasomotor  center,  just  as  the 
natural  remedy  for  arterial  anoxaemia  due,  say,  to  low  atmos- 
pheric pressure,  appears  at  first  sight  to  be  increased  breathing 
and  increased  circulation  rate.  But  just  as  the  increased  breathing 
and  circulation  rate  in  arterial  anoxaemia  is  to  a  large  extent  pre- 
vented by  the  counter-balancing  effect  of  the  alkalosis  thereby 
produced,  so  also  is  the  full  pressor  response  to  anoxaemia  due  to 
fall  in  blood  pressure.  The  breathing  is  already  stimulated  by  the 
diminished  blood  circulation  in  the  brain,  so  that  the  arterial 
blood  is  so  alkaline  as  to  quiet  down  the  vasomotor  center,  in  spite 
of  the  anoxaemia.  Benefit  may  be  expected  from  the  administra- 
tion of  CO2  or  even  of  acids ;  but  the  main  need  is  for  increase  in 
the  volume  of  the  blood.  This  increase  comes  naturally,  provided 


288  RESPIRATION 

that  fluid  is  supplied ;  and  the  great  thirst  which  results  from  loss 
of  blood  is  an  expression  of  the  need  for  fluid.  But  time  is  required 
for  this  natural  process  of  recuperation,  and  meanwhile  the  patient 
may  die. 

Fluid  may  be  supplied  quickly  by  the  intravenous  injection  of 
Ringer's  Solution,  but  this  plan  is  rather  ineffective,  since  the 
injected  liquid  leaks  out  from  the  vessels  quickly.  Bayliss  there- 
fore introduced  his  now  well-known  gum-saline  solution  for  use 
in  cases  of  loss  of  blood  and  similar  conditions.23  The  gum  does 
not  leak  out  at  all  readily  from  the  vessels,  and  in  virtue  of  the 
osmotic  pressure  which  it  produces  it  keeps  the  salt  solution  from 
leaking  out.  The  gum  thus  plays  the  same  part  in  this  respect  as 
the  proteins  of  the  blood  plasma,  but  is  free  from  the  occasional 
toxic  properties  of  the  proteins  in  blood  transfused  from  another 
person,  although  it  seems  to  be  sometimes  not  free  from  disadvan- 
tages. It  might  seem  at  first  sight  as  if  the  injection  of  gum  saline 
must,  other  things  being  equal,  be  very  inferior  in  its  effects  to 
transfusion  of  blood,  since  there  is  no  haemoglobin  in  the  salt  solu- 
tion. But  unless  the  loss  of  blood  has  been  enormous  there  is  no 
great  need  for  haemoglobin.  Increased  rate  of  circulation  will 
make  up  for  diminished  power  of  the  blood  to  carry  oxygen  and 
CO2,  as  explained  more  fully  on  page  293. 

The  conditions  known  as  "wound-shock,"  "surgical  shock," 
"anaesthetics  shock,"  and  shock  from  burns,  have  given  rise  to 
much  discussion  and  investigation.  When  "shock"  is  fully  de- 
veloped, the  arterial  blood  pressure  is  very  low,  the  pulse  feeble, 
the  lips  and  skin  leaden  colored,  and  the  breathing  shallow  and 
often  rapid,  or  sometimes  periodic.  It  appears  at  present  as  if  this 
general  condition  can  be  brought  about  in  several  different  ways; 
and  Yandell  Henderson's  investigations  have  thrown  a  clear  light 
on  certain  of  the  causes  of  shock.  It  will  be  convenient  to  consider 
these  first. 

He  showed  in  the  first  place  that  a  condition  of  shock  can  be 
brought  about  in  animals  by  continued  excessive  ventilation  of  the 
lungs.  This  of  course  greatly  reduces  the  CO2  in  the  arterial 
blood,  thus  producing  a  state  of  alkalosis.  The  response  to  this  is 
slowing  of  the  circulation,  and  consequent  great  anoxaemia,  as 
already  explained.  The  slowing  of  the  circulation  tends,  of  course, 
to  diminish  the  alkalosis  in  the  tissues,  but  only  at  the  expense  of 
producing  most  formidable  anoxaemia.  The  alkalosis  is  also  com- 

23  Bayliss,  Intravenous  Injection  in  Wound  Shock,  1918. 


RESPIRATION  289 

bated  by  the  body  in  other  ways,  one  being  the  prompt  stoppage 
of  ammonia  formation  and  the  excretion  of  alkaline  urine,  as 
already  explained ;  and,  whether  in  consequence  of  this  or  of  other 
causes,  the  so-called  "alkaline  reserve"  of  the  blood  decreases 
greatly,  as  Henderson  and  Haggard  showed  (Chapter  VIII). 
Nevertheless  the  anoxaemia  and  alkalosis  cannot  be  overcome. 
The  circulation  rate  steadily  diminishes;  the  heart,  in  consequence, 
probably,  of  anoxaemia,  begins  to  fail,  apart  altogether  from  its 
inadequate  supply  of  venous  blood ;  and  finally  there  is  complete 
failure  of  the  heart.  If,  however,  the  forced  breathing  is  stopped 
before  cardiac  failure  has  occurred,  death  may  occur  from  pro- 
longed apnoea  and  consequent  acute  asphyxia,  as  mentioned  in 
Chapter  II.  When  the  condition  of  shock  has  developed  suffi- 
ciently, the  animal  cannot  be  saved  by  adding  CO2  to  the  air 
breathed ;  but  in  the  earlier  stages  this  procedure  is  quite  effective. 
The  hopeless  condition  to  which  the  animal  is  reduced  by  the 
forced  artificial  respiration  is  probably  analogous  to  the  condition 
produced  in  various  ways  by  prolonged  anoxaemia,  as  in  very 
severe  CO  poisoning,  or  in  a  patient  who  has  been  allowed  to 
suffer  for  long  from  severe  arterial  anoxaemia.  It  is  probably  the 
anoxaemia  rather  than  the  alkalosis  that  produces  the  serious 
effect,  since,  as  already  mentioned,  forced  breathing  of  oxygen  is 
more  easily  tolerated  than  forced  breathing  of  air. 

A  condition  of  shock  produced  by  forced  artificial  respiration 
is,  of  course,  not  a  natural  occurrence;  but  Henderson  showed 
that  excessive  respiration  can  be  produced  by  natural  means  in 
two  ways :  firstly,  by  powerful  afferent  stimuli,  as  by  electrical 
stimulation  of  the  sciatic  nerve,  even  in  the  presence  of  anaesthesia 
sufficient  to  abolish  consciousness ;  and  secondly,  by  the  action  of 
ether  in  doses  not  sufficient  to  anaesthetize  an  animal  completely. 
The  afferent  stimuli,  or  the  ether,  increase  the  breathing  to  such 
an  extent  as  to  diminish  greatly  the  CO2  in  the  arterial  blood, 
thus  producing  great  alkalosis  or  acapnia,  with  concomitant  anox- 
aemia. By  these  means,  therefore,  a  condition  of  shock  may  easily 
be  produced  in  a  patient;  and  it  seems  probable  that  in  this  way 
the  condition  generally  known  as  shock  is  frequently  produced  as 
a  matter  of  fact. 

Clinical  evidence  seems,  nevertheless,  to  indicate  that  in  many 
ordinary  cases  of  wound  shock  there  has  been  no  excessive 
breathing.  On  the  other  hand  there  are  many  facts  indicating 
that  the  symptoms  are  due  to  absorption  from  injured  tissues  of 


290  RESPIRATION 

harmful  disintegration  products,24  and  Dale  and  Laidlaw  have 
shown  that  similar  symptoms  are  caused  by  the  action  of  histamine 
produced  by  tissue  disintegration.25  In  "histamine  shock"  the 
venous  return  to  the  heart  is  inadequate,  just  as  in  acapnial  shock, 
and  blood  appears  to  stagnate  in  dilated  capillaries  so  that  the 
rest  of  the  vascular  system  is  imperfectly  filled  with  blood.  Dale 
and  Laidlaw  regard  the  dilatation  of  capillaries  as  a  primary  ac- 
tion of  the  poison.  The  respiratory  center  seems,  also,  to  be  affected 
very  quickly,  so  that  artificial  respiration  is  needed  to  keep  the 
animal  alive.  How  far  the  failure  of  the  respiratory  center  is 
consequent  on  failure  of  the  circulation,  or  vice  versa,  it  seems 
difficult  at  present  to  say ;  but  the  shallow  breathing  and  leaden 
cyanosis  in  shock  are  indicative  of  advancing  failure  of  the  re- 
spiratory center,  and  appear  to  be  clear  indications  for  early 
and  continuous  oxygen  administration,  if  the  condition  cannot  be 
dealt  with  by  removing  its  cause  or  in  other  ways.  To  remedy  the 
imperfect  filling  of  the  vessels  and  consequent  failure  of  the  circu- 
lation, there  is  an  equally  clear  indication  for  the  intravenous 
injection  of  gum-saline  solution.  Whether  the  administration  of 
air  containing  CO2  would  be  of  service,  as  in  shock  due  to  simple 
alkalosis,  is  not  yet  known.  If  the  respiratory  center  is  injured  by 
a  poison  from  the  injured  tissues  it  may  be  unable  to  respond 
properly  to  the  CO2. 

Dale  found  that  the  danger  from  histamine  shock  may  be  enor- 
mously increased  by  the  administration  of  an  anaesthetic.  Many  of 
Henderson's  observations  seem  to  point  in  the  same  direction  as 
regards  acapnic  shock.  These  investigations  throw  much  light  on 
the  fatal  accidents  of  anaesthesia. 

In  connection  with  circulation  and  breathing  it  is  important  to 
consider  the  manner  in  which  the  volume  and  haemoglobin  per- 
centage of  the  blood  adjust  themselves  under  varying  conditions. 
They  are  fairly  constant  within  about  five  per  cent  under  ordinary 
conditions  for  any  individual,  and  the  volume  of  blood  in  a  mam- 
mal bears  a  pretty  constant  ratio  to  the  body  weight.  This  propor- 
tion does  not  depend  upon  size  or  ratio  of  body  weight  to  surface, 
since  it  is  about  the  same  in  large  as  in  small  mammals.  Thus 
in  the  rat  or  mouse  the  proportion  is  about  the  same  as  in  man. 

In  a  small  warm-blooded  animal  such  as  a  mouse  the  metabolism 
per  gram  of  body  weight  is  enormously  greater  than  in  a  large 

84 Report  No.  VIII  of  Surgical  Shock  Committee  (Special  Report  No.  26  of 
Medical  Research  Committee),  1919. 

"Dale  and  Laidlaw,  Journ.  of  Physiol.,  LII,  p.  355,  1919. 


RESPIRATION 


291 


animal  such  as  a  man,  and  roughly  speaking  is  proportional  to 
the  ratio  of  external  surface  to  body  weight.  As  was  shown  by 
Dr.  Florence  Buchanan,26  the  pulse  rate  and  respiration  rate  vary 
in  about  the  same  proportion.  Thus  in  a  canary  the  pulse  rate,  as 
recorded  photographically  by  means  of  the  capillary  electrometer, 
was  about  1,000  per  minute,  the  rate,  as  compared  with  that  in 
man,  being  greater  in  proportion  to  the  more  rapid  metabolism. 
The  circulation  rate  in  a  small  animal  is  thus  enormously  greater 
than  in  a  large  animal,  and  indeed  must  be  so ;  but  the  proportions 


12.0 


10-0 


S-o 


6.0 


4.0 


2.0 


40O 


600          1200          I60O         200O         2400       2BOO 

Weight  of  Rabbits  in  Grammes 


szoo 


Figure  71. 

Blood  volumes  of  rabbits  in  cc.  of  blood  per  100  grams  of  body  weight. 
The  curve  shows  what  the  blood  volumes  would  be  if  they  varied  in  the  pro- 
portion of  body  surface  to  body  weight.  The  dots  and  crosses  show  average 
results  of  actual  determinations  by  the  modified  Welcker  method.  Dots  repre- 
sent results  of  Boycott :  crosses  of  Dreyer  and  Ray.  The  numbers  indicate 
number  of  determinations  for  each  group  of  observations. 

between  the  different  parts  of  animals,  including  the  blood,  do 
not  depend  on  differences  in  size  of  the  animals.  From  a  very 
limited  number  of  experiments  on  animals,  Professor  Dreyer  of 
Oxford27  drew  the  extremely  improbable  conclusion  that  in  ani- 

29  Buchanan,  Science  Progress,  July,  1910. 

"Dreyer  and  Ray,  P kilos.  Trans.  Royal  Society,  B,  CCI,  p.   138,   1910;  also 
Dreyer,  Ray,  and  Walker,  Skand.  Arch.  f.  Physiol.,  28,  p.  299,  1913. 


292  RESPIRATION 

mals  of  the  same  species  the  blood  volume  is  a  function  of  the 
ratio  of  body  surface  to  mass,  and  even  inferred  that  the  carbon 
monoxide  method  of  determining  blood  volume  (appendix) 
must  be  incorrect  because  it  showed  no  such  relation  in  experi- 
ments published  by  Douglas.28  The  matter  was  afterwards  re- 
investigated  in  rats  by  Chisolm,29  and  by  Boycott.30  Figure  71 
shows  the  results  of  Boycott  and  of  Dreyer  (all  obtained  by  the 
modified  Welcker  method)  in  rabbits  of  different  sizes.  It  will 
be  seen  that  there  is  no  difference  between  them,  and  that,  al- 
though young  rabbits  have  usually  a  somewhat  higher  proportion 
of  blood  than  older  ones,  the  increased  proportion  does  not  vary 
with  the  proportion  of  body  weight  to  surface.  The  circulation 
rate  must,  other  things  being  equal,  be  faster  in  a  smaller  animal 
with  its  higher  proportional  metabolism,  but  an  increased  pro- 
portional dead  weight  of  blood  would  be  no  advantage,  but  a 
disadvantage. 

When  the  volume  of  blood  is  reduced  by  considerable  bleeding, 
there  is  at  first  a  fall  in  arterial,  and  doubtless  also  in  venous, 
blood  pressure ;  but  soon  the  blood  pressure  is  restored.  The  first 
effect  of  the  bleeding  is  probably  to  evoke  partial  compensation 
by  a  pressor  excitation  of  the  vasomotor  center.  This  is  probably 
due  to  diminished  circulation  rate  and  consequent  fall  in  oxygen 
pressure  and  increase  of  CO2  pressure  in  the  medulla.  Very  soon, 
however,  the  blood  volume  is  more  or  less  restored  by  taking  up 
of  liquid  from  the  tissues  and  intestines.  The  blood  is  thus  diluted  ; 
but  the  diluted  blood  fills  up  the  blood  vessels  and  completely  re- 
stores the  blood  pressure.  After  a  delay  of  many  days  or  perhaps 
several  weeks,  the  hydraemic  blood  is  restored  to  normal  by  re- 
production of  the  missing  corpuscles. 

Similarly  when  blood  is  transfused  from  another  animal  of 
the  same  species  there  is  at  first  a  rise  of  both  venous  and  arterial 
blood  pressure.  Soon,  however,  the  volume  of  blood  is  reduced 
by  disappearance  of  most  of  the  extra  plasma.  The  remaining 
blood  then  contains  an  excess  of  red  corpuscles,  and  these  are  only 
got  rid  of  in  the  course  of  some  days  or  weeks. 

The  changes  which  occur  were  followed  by  Boycott  and  Doug- 
las with  the  help  of  the  carbon  monoxide  method  of  determining 
the  blood  volume  in  living  animals.31  They  found  that  on  repeated 

28  Douglas,  Journ.  of  Physiol.,  XXXIII,  p.  493,  1906. 

29  Chisolm,  Quart.  Journ.  of  Exper.  Physiol.,  IV,  p.  208,  1911. 

30  Boycott,  Journ.  of  Pathol.  and  Bacter.,  XVI,  p.  485,  1912. 

81  Boycott  and  Douglas,  Journ.  of  Pathol.  and  Bacter.,  XIII,  p.  270,  1909. 


RESPIRATION 


293 


bleeding  the  reproduction  of  the  red  corpuscles  becomes  more  and 
more  rapid,  so  that  finally  the  animal  can  reproduce  the  lostxor- 
puscles  very  rapidly.  Similarly  on  repeated  transfusion  the  animal 
can  get  rid  of  the  transfused  corpuscles  more  and  more  rapidly. 
It  thus  becomes  adapted  to  either  bleeding  or  transfusion. 

In  an  animal  in  which  as  a  result  of  bleeding  or  similar  causes 
the  proportion  of  haemoglobin  in  the  blood  is  abnormally  low  the 
oxygen  pressure  must  fall  more  rapidly  than  usual  if  the  rate  of 
circulation  is  unaltered,  as  the  blood  passes  through  the  tissues. 
In  accordance  with  what  has  been  already  said,  this  will  naturally 
tend  to  be  more  or  less  compensated  for  by  an  increased  rate  of 
circulation.  But  this  can  occur  freely  without  the  opposing  effect 
due  to  the  production  of  alkalosis,  since  owing  to  the  diminished 
percentage  of  haemoglobin  the  pressure  of  CO2  would  also  be 


OXFOGD 

1 
P 

SUMMIT  OF   PIKES  PEAK 

COLORADO 
SPRINGS 

NEW  HAVEN 

OXFORD 

HALDANE 


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Figure  72. 

Ordinates  represent  percentages  of  the  average  haemoglobin  percentages 
obtained  before  ascending  the  Peak  (Oxford  and  Colorado  Springs)  on  the 
particular  subject.  Continuous  thick  line  =  total  oxygen  capacity  or  total 
amount  of  haemoglobin.  Continuous  thin  line  =  percentage  of  haemoglobin. 
Interrupted  line  =  blood  volume.  The  values  in  Oxford  before  the  start  of 
the  expedition  are  plotted  without  relation  to  time. 

too  high  unless  the  circulation  rate  were  increased.  An  increased 
circulation  rate  is  thus  the  natural  response  to  a  diminished  haemo- 
globin percentage. 

We  know  from  observations  on  persons  living  at  high  altitude 
that  one  result  of  the  shortage  of  oxygen  caused  by  the  diminished 
barometric  pressure  is  that  the  percentage  of  haemoglobin  and  of 
red  corpuscles  in  the  blood  rises  (see  Chapter  XIII).  In  different 
individuals  the  rise  varies  considerably.  Thus  in  persons  who  had 
been  living  for  some  weeks  on  the  summit  of  Pike's  Peak  we  found 
that  the  haemoglobin  percentage  varied  from  113  to  153  per  cent 
of  the  normal.  The  rapidity  with  which  the  change  occurs  varies 
also  greatly  in  different  individuals.  Figure  72  shows  the  rate 


294 


RESPIRATION 


at  which  the  change  occurred  and  disappeared  in  one  of  the 
members  of  the  Pike's  Peak  expedition,  and  Figure  73  shows  the 
far  faster  rate  of  increase  in  haemoglobin  in  Mr.  Richards,  a 
mining  engineer  who  kindly  made  for  me  a  careful  series  of 


observations  on  himself  on  going  to  a  mine  in  Bolivia  at  a  height 
of  15,000  feet.  Figure  72  also  shows  the  changes  in  blood  volume 
and  total  haemoglobin  in  the  body  (total  oxygen  capacity).  It 
will  be  seen  that  after  the  first  few  days  the  blood  volume  in- 


RESPIRATION  295 

creases,  so  that  the  total  haemoglobin  in  the  body  increases  more 
than  the  percentage  of  haemoglobin.  Thus  the  corpuscles  dcrnot 
simply  increase  at  the  expense  of  the  space  occupied  by  plasma, 
but  the  total  space  occupied  by  the  blood  is  increased.  It  seems 
probable,  however,  that  when  a  rapid  increase  in  the  percentage 
of  haemoglobin  occurs,  as  shown  in  Figure  73,  the  increase  is 
mainly  brought  about  at  first  by  disappearance  of  plasma  owing 
to  a  pressor  reaction  of  the  vasomotor  center,  with  consequent  in- 
creased filling  of  the  capillaries  and  resulting  loss  of  liquid  from 
the  blood.  In  acute  anoxaemia  produced  by  asphyxial  conditions 
there  appears  to  be  a  rapid  loss  of  fluid  from  the  blood,  and  this 
is  probably  due  to  a  pressor  reaction.  Schneider  and  his  colleagues 
have  recently  observed  that  in  a  considerable  proportion  of  airmen 
exposed  for  a  quite  short  time  to  low  pressures  of  oxygen  there  is 
a  small  but  quite  appreciable  rise  in  the  haemoglobin  percentage.32 

There  appears  to  be  no  doubt  that  the  cause  of  the  increased 
total  amount  of  haemoglobin  and  red  corpuscles  in  the  body  at 
high  altitudes  is  increased  activity  of  the  bone  marrow  in  forming 
red  corpuscles.  On  this  point  direct  evidence  was  obtained  by 
Zuntz  and  his  colleagues.33  They  found  that  in  dogs  the  blood- 
forming  red  marrow  was  markedly  increased  at  a  high  altitude. 
The  stimulus  to  this  increase  was  undoubtedly  fall  in  the  oxygen 
pressure  of  the  blood,  and  it  is  doubtless  in  the  same  way  that  in- 
creased formation  of  red  corpuscles  is  brought  about  by  loss  of 
blood,  especially  if  repeated.  From  the  experiments  of  Boycott  and 
Douglas  on  repeated  blood  transfusions,  we  can  also  infer  with 
great  probability  that  with  increased  oxygen  pressure  in  the  tis- 
sue capillaries,  owing  to  an  increased  proportion  of  haemoglobin, 
there  is  a  corresponding  increase  in  the  blood-destroying  tissues. 
The  proportion  of  haemoglobin  in  the  blood  appears,  therefore, 
to  be  dependent  on  the  oxygen  pressure  in  tissue  capillaries.  This 
inference  is  confirmed  by  the  fact  that,  as  Nasmith  and  Graham 
showed,34  the  haemoglobin  percentage  rises  markedly  in  animals 
which  are  kept  exposed  to  a  small  percentage  of  CO. 

In  cases  of  chronic  heart  disease,  and  more  particularly  in  cases 
of  congenital  heart  defects  accompanied  by  cyanosis,  there  is  often 
a  great  increase  in  the  total  haemoglobin  and  also  in  the  blood 
volume.  Thus  in  a  congenital  case  of  "Morbus  coeruleus,"  brought 

82  Gregg,  Lutz,  and  Schneider,  Amer.  Journ.  of  Physiol.,  L,  p.  216,  1919. 

33  Zuntz,    Loewy,    Muller,    and    Caspar!,    Hohenklima    und    Bergwanderungen, 
Berlin,  1906. 

34  Nasmith  and  Graham,  Journ.  of  Physwl.,  XXXV,  p.  32,  1906. 


296  RESPIRATION 

to  us  by  Dr.  Parkes  Weber,  Douglas  and  I  found  that  the  haemo- 
globin percentage  was  increased  80  per  cent;  the  blood  volume 
IOO  per  cent;  and  the  total  haemoglobin  260  per  cent;35  and  we 
found  similar  increases  in  another  case.  Lorrain  Smith  had  al- 
ready found  a  considerable  increase  in  a  non-congenital  heart 
case  with  chronic  cyanosis.36 

In  some  cases  (so-called  idiopathic  polycythaemia)  where  there 
is  neither  exposure  to  a  lowered  oxygen  pressure  nor  any  heart 
or  lung  affection,  the  haemoglobin  percentage  and  number  of 
red  corpuscles  per  unit  volume  is  greatly  increased.  On  determin- 
ing the  blood  volume  in  two  of  these  cases  I  found  it  greatly  in- 
creased. Boycott  and  Douglas  examined  three  other  cases  with 
a  similar  result.37  In  the  most  marked  of  these  cases  the  haemo- 
globin percentage  was  1 76  per  cent  of  the  normal,  and  the  blood 
volume  nearly  three  times  the  normal,  so  that  the  amount  of 
haemoglobin  in  the  body  was  about  five  times  the  normal.  Idio- 
pathic polycythaemia  is  accompanied  by  a  bluish  tint  of  the  skin, 
and  this  suggests  that  from  some  cause  there  is  slowing  of  the 
circulation  and  consequent  anoxaemia  of  the  tissues,  to  which  the 
increased  haemoglobin  percentage  is  a  natural  response. 

It  is  clear  that  increase  in  the  haemoglobin  percentage  will  tend 
to  diminish  the  tissue  anoxaemia  at  high  altitudes  or  in  cases  of 
heart  affections;  for  the  blood  can  pass  more  slowly  (or  at  a  more 
normal  rate  at  high  altitudes)  through  the  capillaries  before  a 
given  fall  in  the  oxygen  pressure  occurs.  This  compensation  is 
never  complete,  however;  for  if  it  were  there  would  be  no  stimu- 
lus to  the  increased  concentration  of  haemoglobin.  An  undue  rise 
of  CO2  pressure  in  the  tissues  is  also  prevented  by  the  increased 
haemoglobin  percentage. 

When  the  red  corpuscles  and  haemoglobin  are  increased  60  or 
80  per  cent  the  viscosity  of  the  blood  is  very  greatly  increased, 
and  a  good  deal  of  stress  has  been  laid  on  this  increased  viscosity 
as  a  hindrance  to  circulation.  Nevertheless  persons  with  their  hae- 
moglobin percentage  increased  50  per  cent  at  high  altitudes  are 
capable  of  the  severest  muscular  exertion ;  and  there  is  no  indica- 
tion in  them  of  any  circulatory  impairment.  When  we  consider 
the  manner  in  which  the  circulation  is  normally  regulated,  as 

"The  details  of  this  case  are  given  by  Parkes  Weber  and  Dorner,  Lancet, 
Jan.  21,  1911. 

38  Lorrain  Smith  and  McKisack,  Trans.  Path.  Soc.  of  London,  LIII,  p.  136, 
1902. 

87  Boycott  and  Douglas,  Guy's  Hospital  Reports,  LXII,  p.   157. 


RESPIRATION  297 

explained  above,  it  seems  evident  that  anything  but  a  very  ex- 
treme increase  in  viscosity  will  at  once  be  compensated  for  by 
more  free  opening  of  arterioles  and  capillaries.  The  resistance 
to  flow  of  blood  in  the  living  body  is  regulated  physiologically, 
and  cannot  for  a  moment  be  compared  to  the  mechanical  resist- 
ance in  a  system  of  lifeless  tubes. 

The  rapid  variations  in  blood  volume  from  diminution  or  in- 
crease in  the  vasoconstrictor  (pressor)  influence  of  the  vaso- 
motor  center  is  perhaps  shown  most  strikingly  by  the  effects  on 
the  blood  of  section  of  the  spinal  cord  below  the  vasomotor  center 
in  the  medulla.  Cohnstein  and  Zuntz  found  that  very  quickly 
after  section  and  consequent  fall  of  blood  pressure  the  proportion 
of  red  corpuscles  fell  to  about  half,  while  the  proportion  rose 
rapidly  again  on  stimulation  of  the  cord  just  below  the  section, 
with  consequent  rise  of  blood  pressure.38  The  blood  appears  to 
take  up.  or  lose  plasma  rapidly  when  the  capacity  of  the  blood 
vessels  is  diminished  or  increased. 

It  was  discovered  by  Lorrain  Smith  with  the  help  of  the  carbon 
monoxide  method  that  in  chlorosis  and  in  secondary  "anaemias" 
the  blood  volume  is  increased  without  any  diminution,  or  with 
only  a  very  slight  one,  in  the  total  haemoglobin  in  the  blood.  The 
anaemia  is  thus  in  reality  a  hydraemia  or  dilution  of  the  haemo- 
globin.39 Boycott  and  I  found  the  same  condition  in  the  ''anaemia" 
of  ankylostomiasis.40  Miss  FitzGerald  found  later  that  in  chlorosis 
the  alveolar  CO2  pressure  is  not  diminished  but  normal,  so  that 
in  this  form  of  anaemia  there  appears  to  be  no  anoxaemia  during 
rest.41  These  facts  suggest  that  the  apparent  anaemia  is  due  to 
some  cause  leading  to  abnormal  dilation  and  consequent  increased 
capacity  of  the  blood  vessels,  with  the  natural  sequence  of  hydrae- 
mia, but  so  that  the  oxygen  pressure  in  the  tissues  is  not  dimin- 
ished. Possibly,  therefore,  the  anaemia  is  produced  through  the 
vasomotor  nervous  system,  or  through  substances,  or  the  deficiency 
of  substances,  which  act  primarily  on  the  blood  vessels.  The  facts 
that  salts  of  iron  have  a  striking  curative  action  in  chlorosis,  and 
that  iron  is  a  constituent  of  haemoglobin,  have  led  to  the  idea  that 
the  anaemia  is  caused  by  the  absence  of  sufficient  iron  for  a  normal 
formation  of  haemoglobin;  but  in  the  cure  of  chlorosis  by  iron 
Lorrain  Smith  could  find  no  appreciable  increase  in  the  total 

38  Cohnstein  and  Zuntz,  P finger's  Archiv.,  88,  p.  310,  1888. 

39  Lorrain  Smith,  Trans.  Pathol.  Soc.  of  London,  LI,  p.  311,  1900. 

40  Boycott  and  Haldane,  Journ.  of  Hygiene,  III,  p.  112,  1903. 

41  FitzGerald,  Journ.  of  Pathol.  and  Bacterial.,  XIV,  p.  328,  1910. 


298  RESPIRATION 

amount  of  haemoglobin  in  the  body.  The  characteristic  dyspnoea 
and  faintness  on  exertion  in  chlorosis,  etc.,  are  probably  due  to 
the  impossibility  of  sufficiently  increasing  during  exertion  the 
already  greatly  increased  circulation. 

In  pernicious  anaemia  and  the  anaemia  of  haemorrhage,  Lor- 
rain  Smith  found  a  very  marked  diminution  of  the  total  haemo- 
globin present ;  but  often  enough  the  blood  volume  was  increased 
above  normal. 

Although  the  intimate  connection  between  breathing  and  cir- 
culation is  already  very  evident,  many  points  in  the  connection 
are  still  uncertain  or  obscure.  There  is  an  abundant  field  for 
clinical  and  physiological  investigation  in  elucidating  this  sub- 
ject, though  it  must  always  be  remembered  that  not  only  are 
breathing  and  circulation  closely  dependent  on  one  another,  but 
they  are  dependent  also  on  other  physiological  activities. 

Addendum.  The  experiments  by  Douglas  and  myself  on  the 
regulation  of  the  circulation  in  man  have  now  been  completed,  and 
are  in  course  of  publication.  A  very  complete  series,  in  which 
Douglas  was  himself  the  subject,  shows  that  during  complete  rest 
the  mixed  venous  blood  had  only  utilized  about  19  per  cent  of  its 
available  oxygen,  and  gained  a  corresponding  charge  of  CO2- 
During  hard  work,  with  the  oxygen  consumption  increased  about 
nine  times,  about  65  per  cent  of  the  arterial  oxygen  was  utilized. 
The  pulse  rate  was  increased  about  2.6  times,  and  as  the  utiliza- 
tion of  the  arterial  oxygen  was  increased  3.4  times,  the  output  of 
blood  per  heartbeat  was  practically  the  same  during  hard  work 
as  at  complete  rest,  and  the  blood  flow  had  simply  increased  in 
proportion  to  the  increase  of  pulse  rate. 

Various  other  subjects,  including  myself,  had  a  similar  high 
rate  of  blood  flow  (about  8  liters  per  minute)  during  rest,  but  one 
or  two  had  a  markedly  lower  rate  of  flow,  with  the  percentage 
utilization  of  oxygen  as  high,  in  one  case,  as  33  per  cent.  In  this 
case  the  output  per  beat  during  rest,  and  the  circulation  rate  (about 
4.7  liters  per  minute)  were  a  good  deal  lower  than  in  the  other 
subjects,  but  the  output  per  beat  increased  to  about  double  during 
hard  work.  There  are  thus  considerable  individual  differences 
(quite  apart  from  differences  in  weight)  as  regards  the  rate  of 
general  blood  flow  and  the  particular  manner  in  which  the  circu- 
lation adapts  itself  to  varying  amounts  of  work. 

As  some  doubt  has  arisen  lately  as  to  whether  oxygenation  of 
blood  within  the  living  body  has  the  same  influence  on  the  CO2 


RESPIRATION  299 

carrying  power  of  blood  as  after  the  blood  has  been  removed  and 
defibrinated,  we  made  careful  observations  on  this  point.  The 
experiments  showed  clearly  that  oxygenation  produces  the  same 
effect  in  the  living  body  as  outside  it. 

A  full  account  of  the  method,  and  of  the  results  reached  by  it, 
will  be  found  in  our  paper. 


CHAPTER  XI 
Air  of  Abnormal  Composition. 

IN  the  present  chapter  I  propose  to  describe  the  mode  of  occur- 
rence and  physiological  effects  of  the  more  commonly  occurring 
gaseous  constituents  of  air.  The  number  of  noxious  gases,  vapors, 
and  particulate  impurities,  which  may,  under  particular  circum- 
stances, be  present  in  air,  is  of  course  very  large,  and  only  the 
commoner  additions  to  air  can  be  dealt  with  here. 

Outside  Air.  Pure  country  air,  freed  from  moisture,  contains 
20.93  per  cent  by  volume  of  oxygen,  .03  per  cent  of  carbon  diox- 
ide, and  79.04  per  cent  of  a  residue  usually  designated  as  "nitro- 
gen," although  of  this  79.04  per  cent  about  .94  per  cent  consists 
of  argon.  Very  minute  traces  are  also  present  of  hydrogen  and 
various  rare  gases.  Ordinary  atmospheric  air  contains,  however, 
aqueous  vapor  in  varying  proportions ;  and  about  I  per  cent  is  on 
an  average  present  in  a  climate  such  as  that  of  Great  Britain.  The 
composition  of  dry  country  air  is  the  same  to  the  second  decimal 
point  all  over  the  world.  In  summer  weather  the  percentage  of 
CO 2  near  the  ground  may  be  as  low  as  .025  during  the  day,  and 
as  high  as  .035  during  the  night,  owing  to  the  influence  of  vegeta- 
tion, etc. ;  and  doubtless  the  oxygen  percentage  rises  or  falls 
correspondingly,  though  this  has  not  yet  been  shown  directly. 

In  towns  the  composition  of  the  outside  air  varies  surprisingly 
little  from  that  in  the  country.  The  percentage  of  CO2  seldom 
rises  above  .05,  nor  does  that  of  oxygen  fall  below  20.9,  even  in  a 
large  town,  like  London ;  and  in  summer  weather  there  is  hardly 
any  difference  between  the  oxygen  and  CO2  percentages  of  town 
and  country  air.  In  a  London  park  on  a  summer  day  the  per- 
centage of  CO2  may  fall  quite  as  low  as  in  the  country.  Consider- 
ing the  great  area  of  a  town  like  London,  and  the  enormous 
quantity  of  coal  and  gas  burnt,  this  fact  is  very  striking,  and 
shows  clearly  that  apart  from  horizontally-flowing  wind  there 
are  very  active  up-and-down  movements  of  the  air,  and  these 
keep  the  air  of  a  town  pure.  It  is  only  in  foggy  weather  that  these 
up-and-down  movements  cease  more  or  less;  and  then  the  im- 
purities in  the  air  of  a  large  and  smoky  town  may  become  very 


RESPIRATION  301 

appreciable.  Russell  found,  for  example,  that  in  London  the  per- 
centage of  CO 2  might  rise  to  0.14  during  a  dense  fog. 

Along  with  CO2  there  are  present  in  the  air  of  towns  a  number 
of  other  impurities.  From  fires  a  good  deal  of  unburnt  CO  passes 
off.  In  the  air  of  the  underground  railways  when  steam  loco- 
motives were  still  used,  I  found  that  about  I  volume  of  CO  was 
present  for  every  12  volumes  of  CO2.  If  we  assume  the  same  pro- 
portion for  the  air  of  a  town,  there  would  be  about  .01  per  cent 
of  CO  present  in  the  air  of  a  bad  London  fog.  This  would  be 
sufficient  in  time  to  saturate  the  haemoglobin  with  CO  to  the  ex- 
tent of  about  17  per  cent,  and  might  thus  produce  appreciable 
effects  on  persons  already  in  bad  health,  though  healthy  persons 
would  not  notice  any  effect. 

Much  more  appreciable,  however,  are  the  effects  of  the  par- 
ticulate  impurities.  Ordinary  coal  contains  a  good  deal  of  sul- 
phur; and  the  sulphur,  in  the  process  of  combustion,  is  mainly 
oxidized  to  sulphuric  acid,  which  condenses  along  with  water 
in  the  form  of  minute  droplets  and  thus  helps  to  form  fog.  Of  the 
unpleasant  irritant  effects  of  this  sulphuric  acid  one  can  form  a 
good  idea  in  passing  through  a  railway  tunnel,  particularly  if  the 
train  is  moving  slowly  up  an  incline  and  the  coal  burnt  contains 
much  sulphur.  Those  familiar  with  sulphuric  acid  fumes  in  chemi- 
cal laboratories  or  factories  will  at  once  recognize  them  in  the 
tunnel  air.  When  badly  purified  lighting  gas  is  burnt  in  a  room, 
the  same  irritant  effect  is  also  noticeable  to  a  less  degree.  In  a  bad 
fog  in  a  large  town  the  choking  effects  of  sulphuric  acid  con- 
tribute largely  to  the  unpleasant  effect  of  the  fog  and  the  manner 
in  which  the  fogginess  of  the  air  persists  even  when  the  air  is 
warmed  in  the  interior  of  a  house.  There  is  no  escape  from  this 
effect  unless  the  air  is  scrubbed  or  filtered.  The  sulphuric  acid  is 
also  destructive  to  metal  and  other  materials. 

Besides  sulphuric  acid  the  smoky  air  contains  particles  of  black 
carbonaceous  matter  which  greatly  help  absorb  the  light,  and 
also  contains  substances  which  have  an  unpleasant  odor  and  more 
or  less  irritant  effect  on  the  air  passages.  As  will  be  shown  below, 
there  is  no  reason  to  believe  that  the  continued  inhalation  of  these 
particles  has  any  deleterious  effect  on  the  lungs,  and  in  ordinary 
town  air  they  are  not  present  in  sufficient  concentration  to  be  of 
any  direct  consequence  in  other  ways  to  health.  Their  greatest 
importance  arises  from  the  inconvenience  and  expense  caused  by 
their  obstruction  of  light  and  the  manner  in  which  they  dirty 
clothes,  walls,  ceilings,  and  everything  else  in  a  house.  By  the 


302  RESPIRATION 

substitution  of  well-purified  gas  for  coal  in  fires,  or  by  smokeless 
combustion  of  coal,  the  trouble  might  be  avoided,  and  indeed  has 
been  much  diminished  within  recent  years. 

Lower  organisms,  and  particularly  plants,  are  on  the  whole 
far  more  sensitive  to  impurities  in  air  and  other  changes  in  en- 
vironment than  higher  animals,  and  particularly  man.  The  real 
reason  for  this  is  that  between  the  living  tissue  elements  and  the 
outside  environment  higher  organisms  possess  an  internal  en- 
vironment which  is  not  only  highly  developed,  but  is  maintained 
with  an  efficiency  which  increases  with  the  scale  in  development. 
Plants  are  extremely  sensitive  to  the  particulate  and  other  impuri- 
ties in  air  and  the  obstruction  of  light  by  smoke  and  opaque  fogs. 
But  few  trees  and  plants  can  flourish  in  the  air  of  a  town  or  in- 
dustrial area.  The  traces  of  acid  and  other  impurities  present  in 
the  air  can  act  more  or  less  directly  on  their  tissue  elements,  which 
have  very  little  between  them  and  the  external  environment. 

Air  of  Occupied  Rooms.  In  rooms  of  all  kinds  where  men  are 
present  the  composition  of  the  air  becomes  altered,  owing  to  res- 
piration and  evaporation  and  to  any  gas  or  oil  lamps  which  may 
be  burning.  Both  respiration  and  lamps  consume  oxygen  and  pro- 
duce CO2  and  moisture.  The  combustion  in  the  lamps  is  perfect, 
so  that  no  CO  passes  into  the  air;  and  unless  the  gas  is  badly 
purified  from  sulphur  the  products  of  combustion  have  very  little 
unpleasant  effect  apart  from  what  may  be  due  to  heat.  It  was 
formerly  supposed  that  some  volatile  toxic  substance  is  given  off 
in  the  breath;  but  the  experimental  evidence  in  support  of  this 
belief  was  found  to  be  fallacious,  and  all  attempts  to  demonstrate 
the  existence  of  such  a  substance  have  failed.  Some  of  the  most 
striking  evidence  on  the  subject  is  afforded  by  experience  in  sub- 
marines, in  which  a  limited  volume  of  air  is  quite  commonly  re- 
breathed  until  after  a  few  hours  a  light  will  not  burn  and  3  per  cent 
or  more  of  CO2  may  be  present.  Provided  the  air  remains  cool,  as 
it  does  in  a  temperate  climate  owing  to  the  cooling  influence  of  the 
water,  the  only  effects  observed  are  those  due  to  CO2. 

Even  in  the  most  crowded  and  ill-ventilated  rooms  the  pro- 
portion of  CO2  seldom  rises  above  0.5  per  cent,  with,  of  course,  a 
corresponding  drop  in  the  oxygen  percentage.  From  the  account 
already  given  of  the  physiology  of  breathing  it  is  evident  that  a 
difference  of  this  order  in  the  composition  of  the  air  is  in  itself  of 
no  appreciable  importance.  The  breathing  simply  becomes  very 
slightly  deeper  and  the  composition  of  the  alveolar  air  and 


RESPIRATION  303 

arterial  blood  remains  practically  unaffected  as  regards  either 
CO2  or  oxygen. 

Although  apart  from  CO2  no  appreciable  amount  of  any 
poisonous  substance  is  given  off  to  the  air  by  the  body,  various 
substances  which  affect  the  olfactory  nerves  are  given  off  in  minute 
amounts  from  persons  or  furniture  in  a  room.  As  a  rule  these  sub- 
stances are  only  perceived  on  entering  a  room,  and  are  not  noticed 
after  a  short  time  by  those  who  remain  in  it.  In  sensitive  persons, 
however,  they  may  produce  an  unpleasant  reflex  effect;  and  for 
this  reason  apart  from  any  other  a  good  ventilation  is  desirable. 
When,  however,  there  is  no  musty  furniture,  and  the  bodies  and 
clothing  of  those  present  are  fairly  clean,  there  is  little  or  no  in- 
convenience from  this  cause. 

A  far  more  important  factor  in  connection  with  the  physio- 
logical effects  of  the  air  in  rooms  is  temperature,  and  along  with 
it  moisture.  The  maintenance  of  a  constant  internal  body  tempera- 
ture depends  on  constant  physiological  adjustment  between  ac- 
tual heat  loss  from  the  body  and  variations  in  environmental  con- 
ditions which  tend  to  make  the  heat  loss  greater  or  less  than  the 
heat  production.  The  variations  in  environmental  conditions  con- 
sist in  variations  in  temperature,  moisture  content,  and  movement 
of  the  air,  and  also  variations  in  the  radiant  heat  gained  or  lost 
by  the  body,  apart  from  the  actual  temperature  of  the  air.  The 
actual  heat  loss  is  regulated  physiologically,  apart  from  conscious 
regulation  by  variation  of  clothing,  etc.,  partly  by  varying  the 
rate  of  blood  circulation  through  the  skin,  and  partly  by  varying 
the  amount  of  water  evaporated  by  the  skin.  The  latter  means  of 
regulation  does  not  come  into  play  unless  the  air  is  warm,  or  heat 
production  in  the  body  is  greatly  increased  by  muscular  exertion. 

When  the  air  of  a  room  is  so  cold,  or  the  movement  of  the  air 
is  so  great,  that  the  skin,  or  parts  of  it,  become  uncomfortably 
cold,  we  are  always  clearly  aware  of  the  cause  of  discomfort.  But 
when  the  air  is  so  warm  as  to  lead  to  the  skin  being  uncomfortably 
warm  we  are  apt  to  attribute  the  discomfort  to  some  other  cause 
than  the  heat.  The  matter  is  also  complicated  by  the  fact  that  in 
different  persons  the  air  temperature  at  which  discomfort  is 
felt  varies  considerably.  Thus  persons  who  have  been  undergoing 
"open-air"  treatment  and  are  accustomed  to  rooms  with  open 
windows  feel  much  discomfort  in  rooms  with  closed  windows 
where  other  persons  are  just  comfortable.  Similarly  Americans 
accustomed  to  the  warm  air  associated  with  central  heating  find 
British  houses  with  fires  very  uncomfortably  cold  in  winter,  while 


304  RESPIRATION 

British  visitors  to  America  find  the  warm  air  of  American  houses 
very  trying. 

The  discomforts  of  warm  or  cold  air  are  not  usually  associated 
with  rise  or  fall  of  internal  body  temperature.  When  suffering 
great  discomfort  from  sitting  in  a  very  cold  room,  I  have  found 
the  rectal  temperature  slightly  raised  rather  than  lowered,  and 
on  going  to  an  uncomfortably  warm  room  there  was  a  slight  fall 
in  rectal  temperature.  Persons  going  unaccustomed  into  very 
warm  air  may  become  faint  or  suffer  from  nausea  or  headache 
without  any  appreciable  rise  of  body  temperature.  There  appears 
to  be  a  fall  of  arterial  pressure  owing  to  failure  on  the  part  of  the 
vasomotor  center  to  compensate  for  the  increased  flow  of  blood 
through  the  skin  in  a  warm  atmosphere,  and  this  probably  ac- 
counts for  the  more  striking  symptoms.  In  any  case  persons  soon 
become  more  or  less  acclimatized  within  limits  to  the  effects  of 
warm  air.  One  can  observe  this  in  miners  who  become  accustomed 
to  warm  places  in  mines,  or  in  people  who  become  accustomed  to 
Turkish  baths. 

It  is  somewhat  noteworthy  that  men  accustomed  to  hard  outdoor 
work  seem  to  be  much  less  sensitive  to  heat  or  cold  indoors  than 
other  persons.  This  is  probably  due  to  the  fact  that  though  they 
are  not  accustomed  to  external  heat  they  are  accustomed  to  what 
in  this  reference  comes  to  much  the  same  thing,  namely,  greatly 
varied  internal  heat  production,  which  involves  the  same  capacity 
for  vasomotor  adaptation  as  exposure  to  external  heat  or  cold. 
Those  who  are  most  affected  by  external  heat  or  cold  indoors  are 
persons  who  are  not  only  unaccustomed  to  external  heat,  but  are 
also  unaccustomed  to  hard  muscular  exertion. 

Part  of  the  discomfort  of  warm  air  in  rooms  is  due  to  its  drying 
effect  on  the  skin  and  particularly  the  upper  air  passage.  Winter 
air  warmed  to  a  temperature  of  about  70° F.  is  very  dry;  and  if 
the  skin  and  upper  air  passages  are  kept  warm  by  the  air  they  lose 
far  more  moisture  than  usual  and  become  uncomfortable.  With 
cold  air  the  inside  of  the  nose  is  kept  cool,  and  during  expiration 
moisture  condenses  in  it,  so  that  it  is  kept  moist  in  spite  of  the  fact 
that  the  cold  air  contains  very  little  moisture.  With  warm  dry  air, 
on  the  other  hand,  there  is  much  evaporation  during  inspiration 
and  little  or  no  condensation  during  expiration,  so  that  the  nose 
is  apt  to  become  very  dry ;  and  this  appears  to  lead  to  swelling  of 
the  mucous  membrane. 

The  combination  of  physiological  disturbances  produced  by 
warm  air  in  a  room  is  apt  to  be  attributed  to  chemical  impurities 


RESPIRATION  305 

in  the  air.  Owing  to  this  fact,  and  general  ignorance  as  to  the 
physiology,  as  distinguished  from  the  chemistry,  of  respiration, 
too  much  stress  was  formerly  laid  on  the  chemical  purity  of  the 
air  in  rooms.  The  chemical  purity  is  nevertheless  a  very  important 
index  of  the  chances  of  infection  through  the  air  from  person  to 
person  in  a  room.  The  more  air  is  passing  through  the  room  the 
less  the  chances  of  infection  become ;  and  for  this  reason  as  high 
as  possible  a  standard  of  chemical  purity  is  desirable  where  a 
number  of  persons,  some  of  whom  may  be  carriers  of  infection, 
are  present.  A  reasonable  standard  to  aim  at  under  these  circum- 
stances is  that  the  excess  of  CO2  in  the  air  of  the  room  should  not 
be  over  .02  per  cent  unless  lights  are  burning,  or  that  about  5° 
cubic  feet  of  air  per  person  and  per  minute  should  be  supplied. 
This  standard  can  easily  be  maintained  in  ordinary  houses  with 
natural  ventilation ;  and  even  in  the  case  of  crowded  buildings  a 
similar  standard  can  be  attained  by  the  right  application  of 
modern  engineering  methods. 

When  air  becomes  very  warm  the  regulation  of  body  tempera- 
ture becomes  dependent  on  increased  evaporation  from  the  skin 
and  not  merely  on  variation  in  the  blood  flow  through  it.  If  mus- 
cular work  is  being  done  this  point  is  soon  reached  if  the  air  is 
fairly  still.  The  amount  of  moisture  in  the  air  then  becomes  very 
important,  as  the  rate  of  evaporation  from  the  skin  depends  on  the 
amount  of  moisture  already  present  in  the  air.  In  still  air,  or  in 
air  moving  at  any  given  rate,  a  temperature  is  finally  reached  at 
which  in  spite  of  profuse  sweating  the  skin  cannot  evaporate 
water  quickly  enough  to  prevent  the  body  temperature  from  rising. 
As  I  showed  experimentally  in  1905,  this  temperature  is  reached 
when  the  wet-bulb  temperature  reaches  a  certain  point.1  Thus  in 
still  air  and  with  hardly  any  clothing,  the  body  temperature  be- 
gins to  rise  when  the  wet-bulb  temperature  exceeds  88 °F  (3i°C). 
It  does  not  matter  what  the  actual  air  temperature  is,  or  the 
actual  percentage  of  moisture  in  the  air,  provided  that  the  wet- 
bulb  temperature  reaches  88°.  Thus  it  was  indifferent  whether  the 
air  temperature  was  88°  with  the  air  saturated,  or  133°  with  the 
air  very  dry,  provided  that  the  wet-bulb  temperature  was  88°. 
When  the  wet-bulb  temperature  was  far  above  88°  the  rate  of 
rise  of  body  temperature  was  proportional  to  the  rise  of  wet-bulb 
temperature.2 

1  Haldane,  Journ.  of  Hygiene,  V,  p.  494,  1905. 

a  Haldane,  Trans.  Inst.  of  Mining  Engineers,  XLVIII,  p.  553,  1914. 


3o6  RESPIRATION 

When  even  moderate  muscular  work  was  being  done  the  criti- 
cal wet-bulb  temperature  was,  even  with  almost  no  clothing,  at 
least  10°  below  88°  in  still  air.  With  the  ordinary  clothing  of 
temperate  climates  the  critical  wet-bulb  temperature  is  much 
lower  than  without  clothing,  especially  during  muscular  work.  On 
the  other  hand,  with  the  air  in  motion,  the  critical  wet-bulb  tem- 
perature is  higher.  The  beneficial  effects  of  fans,  punkahs,  etc., 
during  heat  is  well  known.  With  the  wet-bulb  temperature  above 
the  body  temperature,  however,  the  rise  of  body  temperature  is  the 
more  rapid  the  more  the  air  is  in  motion. 

In  the  climate  of  Great  Britain  the  wet-bulb  shade  temperature 
very  seldom  rises  above  70°,  even  on  very  warm  summer  after- 
noons ;  but  during  heat  waves  in  America  a  wet-bulb  temperature 
of  75°  is  not  infrequently  reached,  and  cases  of  hyperpyrexia 
from  the  heat  then  become  common.  Wet-bulb  temperatures  of 
over  80°  are  of  course  common  in  tropical  countries,  and  are  met 
by  proper  adaptation  of  clothing  and  mode  of  life;  but  the 
amount  of  muscular  exertion  which  is  possible  with  a  wet-bulb 
temperature  over  80°,  except  in  a  good  breeze,  is  limited.  In 
ordinary  rooms  in  a  temperate  climate,  and  when  ordinary  cloth- 
ing is  worn,  a  wet-bulb  temperature  of  even  65°  becomes  oppres- 
sive and  likely  to  cause  fainting  and  headaches  in  persons  not 
accustomed  to  heat  or  heavy  muscular  exertion. 

In  order  to  obtain  a  simultaneous  measure  of  the  cooling  action 
on  the  body  of  air  temperature,  movement  of  air,  and  maximum 
evaporation  from  the  skin,  Dr.  Leonard  Hill  has  devised  an  in- 
strument known  as  the  katathermometer.  This  consists  of  an 
alcohol  thermometer  with  a  very  large  bulb,  which,  when  an  ob- 
servation has  to  be  made,  is  heated  to  about  ioo°F.  The  flask  is 
jacketed  with  an  absorbent  jacket  which  can  be  moistened  with 
water.  By  the  rate  at  which  the  water  cools,  a  comparative  esti- 
mate can  be  obtained  of  the  maximum  possible  combined  cooling 
action  on  the  human  body  of  movement  of  air,  temperature,  and 
evaporation.  The  actual  cooling  effect  of  the  air  depends,  of 
course,  on  the  physiological  responses  of  the  body,  but  cannot  ex- 
ceed the  maximum  shown  by  the  wet  katathermometer. 

The  physiology  of  temperature  regulation  lies  outside  the  scope 
of  this  book;  but  temperature  effects  are  so  liable  to  be  confused 
with  effects  due  to  chemical  impurities  in  air  that  it  seemed 
necessary  to  refer  briefly  to  the  physiological  disturbances  due  to 
warm  air. 

The  air  of  occupied  rooms  is  liable  to  be  contaminated  by 


RESPIRATION  307 

escapes  of  lighting  gas ;  and  under  certain  circumstances  fatal  or 
very  serious  accidents  from  this  cause  may  occur  and  lighting 
gas  may  be  used  very  easily  for  purposes  of  suicide  or  even 
murder.  The  great  majority  of  accidental  deaths  from  poisoning 
by  lighting  gas  have  been  in  bedrooms,  owing  to  the  gas  being  in 
some  way  left  turned  on  after  being  extinguished.  In  1899  a 
Departmental  Committee  of  which  I  was  a  member  reported  on 
the  influence  of  the  use  of  water  gas  in  connection  with  poisoning 
by  lighting  gas,  and  I  investigated  the  conditions  under  which 
poisoning  may  occur  in  bedrooms.3 

It  might  be  supposed  that  the  sense  of  smell  would  always  give 
warning  of  an  escape  of  lighting  gas  in  a  room.  On  going  into  a 
room  in  which  gas  is  escaping  one  notices  the  smell  at  once,  and 
long  before  sufficient  gas  is  present  to  cause  any  symptoms  of 
poisoning;  but  a  person  inside  the  room  when  the  escape  begins 
may  quite  probably  never  notice  it.  The  reason  for  this  is  that 
the  sense  of  smell  for  any  particular  substance  becomes  fatigued 
very  rapidly,  and  if  the  proportion  of  the  odoriferous  substance  in 
the  air  is  only  very  gradually  increased  the  smell  is  never  noticed. 
In  this  way  an  escape  of  gas  in  a  bedroom  is  often  unnoticed. 

When  a  continuous  escape  of  gas  occurs  in  a  room,  the  per- 
centage of  gas  in  the  air  goes  on  increasing  until  the  rate  of  es- 
cape through  walls,  roof,  etc.,  balances  the  rate  of  inflow  of  gas. 
In  any  ordinary  room  the  walls,  roof,  and  floor  are  permeable  to 
air,  and,  if  any  cause  such  as  pressure  of  wind  or  difference  of 
temperature  between  inside  and  outside  tends  to  produce  air 
currents  in  and  out  of  the  room,  the  flow  of  air  is  surprisingly 
free.  If,  for  instance,  the  door  and  windows  are  closed  and  all 
visible  chinks  pasted  up,  it  will  be  noticed  that  when  a  fire  is  lit 
the  chimney  draws  just  as  well  as  before.  Large  volumes  of  air 
are  passing  up  the  chimney,  and  this  air  comes  in  through  the 
walls,  roofs,  etc.  Brick  and  stonework,  for  instance,  are  fairly 
permeable  to  air,  as  can  easily  be  shown  by  suitable  means.  Small 
rooms  in  a  dwelling  house  do  not  require  artificial  ventilation, 
provided  the  passages,  etc.,  are  well  ventilated,  since  the  ratio  of 
surface  to  cubic  capacity  is  high,  so  that  ventilation  through  the 
surfaces  of  the  room  counts  for  more  in  relation  to  the  cubic  space 
per  person  in  the  room. 

It  will  thus  be  readily  seen  that  what  happens  in  a  room  when 
gas  escapes  continuously  will  depend  on  various  circumstances, 
such  as  the  difference  in  temperature  between  inside  and  outside, 

3  Report  of  the  Water-gas  Committee,  Part.  Paper,  1899.  Appendix  i. 


3o8  RESPIRATION 

the  presence  of  a  fire  or  of  central  heating  by  warm  air,  the 
amount  of  wind,  etc.  But  even  if  there  is  little  or  no  cause  of  ex- 
change of  air  before  the  gas  escape  begins,  the  escape  itself  will 
furnish  a  cause,  since  the  gas  is  much  lighter  than  air,  so  that  air 
to  which  gas  has  been  added  will  tend  to  pass  out  by  the  roof. 
Hence  even  under  conditions  least  favorable  to  ventilation,  the 
gas  can  never  accumulate  to  more  than  a  very  limited  concentra- 
tion in  the  air  of  a  room. 

Another  complication  in  connection  with  gas  escapes  is  that  the 
gas  may  or  may  not  mix  evenly  with  the  air  of  a  room.  Gas  escap- 
ing from  a  burner  passes  straight  upwards  to  the  roof  and  there 
spreads.  I  found  that  unless  the  temperature  of  the  windows  and 
walls  was  below  the  air  temperature  of  the  room  the  gas  never 
came  down  again  to  any  very  great  extent.  With  a  very  rapid 
escape  of  gas,  as  when  a  burner  was  completely  removed  or  a 
pipe  cut,  this  was  very  marked.  It  was  impossible  to  obtain  a 
poisonous  atmosphere  at  the  ordinary  breathing  level,  but  there 
was  a  heavy  concentration  of  gas  near  the  roof.  The  danger  of 
poisoning  was  to  persons  in  the  floor  above,  and  not  to  those  in  the 
room  where  the  escape  was  occurring.  Near  the  floor  level,  how- 
ever, a  curious  phenomenon  was  observed.  The  gas  actually 
present  in  the  air  was  found  to  be  nearly  pure  hydrogen.  This 
showed  that  it  was  only  by  diffusion,  and  not  by  convection  cur- 
rents, that  gas  had  penetrated  downwards.  Hydrogen,  being  much 
more  diffusable  than  any  of  the  other  constituents  of  lighting  gas, 
had  diffused  downwards  much  more  rapidly ;  and  in  general  it  was 
found  that  the  hydrogen  in  lighting  gas  separates  off  by  diffusion 
very  readily,  leaving  a  mixture  containing  more  of  CO  and  the 
other  heavier  constituents  of  the  gas.  At  night,  when  the  windows 
were  cold,  and  the  tendency  to  convection  currents  down  them 
was  consequently  strong,  mixture  of  the  gas  by  convection  was 
much  more  apt  to  occur,  especially  if  the  escape  was  at  a  moderate 
rate.  There  was  consequently  more  danger  at  night  to  persons 
sleeping  in  the  room. 

When  the  percentage  of  gas  was  determined  at  intervals  in  the 
air  of  a  room  with  gas  continuously  escaping  from  a  burner  and 
mixing  by  convection  currents  down  the  windows,  I  found  that, 
if  the  conditions  of  wind,  etc.,  remained  constant,  the  percentage 
became  constant  after  a  certain  time  which  depended  on  the  size 
of  the  room  among  other  conditions,  and  might  vary  from  about 
one  to  three  hours  according  to  the  size  of  the  room,  rate  of  gas 
escape,  amount  of  wind,  etc.  The  maximum  percentage  obtained 


RESPIRATION  309 

was  2.7  per  cent  at  the  breathing  level.  With  larger  escapes  of 
gas  this  percentage  could  hardly  be  increased,  as  most  of  the  gas 
remained  at  the  roof.  The  air  at  all  parts  of  the  rooms  tested  was 
examined  with  a  miner's  safety  lamp  to  see  if  the  air  ever  became 
explosive;  but  with  such  escapes  as  could  be  produced  when 
burners  were  not  taken  off,  I  never  succeeded  in  obtaining  an 
explosive  atmosphere  even  at  the  roof.  It  requires  about  8  per 
cent  of  lighting  gas  to  render  air  explosive. 

These  experiments  had  a  very  definite  practical  significance  in 
connection  with  the  composition  of  lighting  gas  used  for  domestic 
purposes :  for  it  is  evident  that  whether  or  not  a  dangerous  result 
will  ensue  from  an  escape  of  gas  in  a  room  will  depend  on  how 
poisonous  the  gas  is,  and  not  simply  on  the  time  during  which  the 
escape  continues.  The  poisonous  action  of  lighting  gas  largely 
diluted  with  air  depends  exclusively  on  the  CO  contained  in  it. 
In  every  case  of  persons  found  dead  in  air  containing  lighting  gas 
the  post  mortem  appearances  are  those  of  CO  poisoning,  and  the 
percentage  saturation  of  blood  as  determined  by  the  method  de- 
scribed in  the  appendix  has  turned  out  to  be  round  80,  just  as  in 
the  case,  referred  to  below,  of  miners  poisoned  by  CO.  Thus, 
broadly  speaking,  the  danger  of  poisoning  from  escape  of  lighting 
gas  depends  on  whether  the  air  will  be  poisonous  from  CO  when 
less  than  2  or  2.5  per  cent  of  gas  is  present. 

Lighting  gas  as  originally  introduced  is  made  by  the  distillation 
of  bituminous  coal,  and  usually  contains  about  7  or  8  per  cent  of 
CO.  With  2  per  cent  of  this  lighting  gas  in  the  air  there  would 
only  be  about  0.14  per  cent  of  CO ;  and  this,  though  a  formidable 
percentage,  would  not,  so  far  as  known,  produce  fatal  effects  in  a 
healthy  person,  as  the  haemoglobin  would,  in  all  probability,  not 
become  much  more  than  about  half -saturated.  To  judge  from  all 
our  present  knowledge,  and  from  the  results  of  experiments  on 
animals,  about  0.3  per  cent  would  usually  be  needed  to  produce 
death  within  a  few  hours. 

Excellent  lighting  gas  can  also  be  made  by  blowing  steam 
through  incandescent  coke  or  coal.  The  product  is  what  is  called 
"blue"  water  gas  consisting  roughly  of  equal  parts  of  hydrogen 
and  CO.  This  gives  a  very  hot,  though  small,  flame,  and  although 
the  flame  by  itself  is  "blue"  and  practically  nonluminous,  an  ex- 
cellent light  is  given  when  a  properly  adjusted  mantle  is  used.  On 
the  other  hand  the  calorific  value  of  a  given  volume  of  this  gas  is 
very  low  as  compared  with  ordinary  coal  gas ;  and  as  the  value  of 
gas  depends  mainly  on  the  heating  power  of  a  given  volume  of  it, 


310  RESPIRATION 

as  well  as,  to  a  certain  extent,  on  the  luminosity  of  its  flame  when 
no  mantle  is  used,  water  gas  is  usually  "carbureted"  by  the  ad- 
dition of  cheap  oil  in  a  chamber  where  the  oil  is  "cracked"  by 
means  of  heat.  The  product  is  known  as  carbureted  water  gas, 
and  is  very  largely  used  as  a  substitute  for  ordinary  coal  gas.  It 
has  a  luminous  flame  and  more  or  less  satisfactory  calorific  value, 
but  contains  about  30  per  cent  of  CO. 

It  is  evident  that  with  gas  containing  30  per  cent  of  CO,  poison- 
ing will  occur  very  readily  with  an  escape  of  gas  during  the  night 
in  a  house.  On  inquiring  into  the  deaths  from  gas  poisoning  in 
American  towns  supplied  with  carbureted  water  gas,  the  com- 
mittee referred  to  above  found  that  about  100  to  200  times  as 
many  deaths  occurred  from  gas  poisoning  with  a  given  distribu- 
tion of  gas  as  in  English  towns  supplied  with  coal  gas  only.  The 
gas  was  also  used  very  extensively  for  purposes  of  suicide,  and 
sometimes  also  as  a  means  of  murder.  Apart  from  actual  danger 
from  poisoning,  there  was  also  the  constant  anxiety  as  to  danger 
from  gas  poisoning.  An  American  mother,  for  instance,  told  me 
that  she  regularly  got  up  every  night  to  make  sure  that  gas  was 
not  escaping  where  her  children  were  sleeping.  The  result  of  the 
committee's  inquiries  was  to  show  that  if  gas  is  to  be  used  for 
domestic  purposes  the  percentage  of  CO  in  it  should  be  reasonably 
low ;  and  in  consequence  of  this  finding  the  use  of  undiluted  car- 
bureted water  gas  was  discontinued  in  Great  Britain,  where, 
indeed,  it  had  only  been  introduced  in  one  or  two  places,  though 
with  unfortunate  results  which  led  to  the  inquiry.  It  should,  how- 
ever, be  mentioned  that  with  the  general  introduction  of  mantles 
the  danger  of  poisoning  from  accidental  escapes  from  burners  is 
considerably  diminished,  as  less  gas  escapes,  and  if  there  is  a 
pilot  flame  the  risk  is  further  greatly  diminished. 

Gas  poisoning  in  houses  may  not  only  occur  from  escapes 
within  the  house,  but  also  from  escapes  from  street  gas  mains; 
and  many  serious  accidents  from  this  cause  have  occurred,  par- 
ticularly with  carbureted  water  gas.  The  danger  is  much  increased 
from  the  fact  that  in  passing  through  earth  the  odoriferous  con- 
stituents (benzene,  etc.)  of  the  gas  are  apt  to  be  more  or  less 
absorbed,  so  that  the  gas  entering  the  basements  of  houses  is  more 
or  less  odorless.  Probably,  also,  it  may  have  lost  a  good  deal  of 
its  hydrogen  by  diffusion,  and  this  will  make  it  more  poisonous. 
A  large  number  of  persons  in  several  houses  and  many  different 
rooms  may  be  poisoned  by  one  serious  breakage  of  a  main. 
Pettenkofer  recorded  an  interesting  case  where,  in  the  times  before 


RESPIRATION  311 

clinical  thermometers,  illness  through  gas  poisoning  from  a  broken 
main  was  mistaken  for  a  peculiar  and  rapidly  infectious  form  uf 
typhus.  No  smell  of  gas  was  noticed  at  first,  and  the  percentage 
of  CO  must  have  been  so  low,  and  perhaps  inconstant,  that  it  took 
some  hours  before  any  distinct  symptoms  of  illness  were  produced. 
At  last  the  smell  became  noticeable,  probably  because  the  earth 
through  which  the  gas  was  escaping  had  become  saturated  with 
the  odoriferous  constituents,  and  so  ceased  to  absorb  them  com- 
pletely. 

Air  of  Mines.  The  air  of  mines  is  liable  to  be  contaminated  by 
various  gases  known  to  British  miners  as  black  damp,  fire  damp, 
afterdamp,  white  damp,  and  smoke.  Of  these,  black  damp  is  the 
commonest  and  most  universally  present;  fire  damp  is  hardly 
found  except  in  connection  with  coal  or  oil;  afterdamp  occurs 
only  after  explosions ;  white  damp  in  connection  with  spontaneous 
heating  of  coal ;  and  smoke  in  connection  with  fires  or  blasting. 

Black  damp  is  distinguished  by  miners  through  its  character- 
istic properties  of  extinguishing  lamps  without  exploding  and 
not  causing  danger  to  life  provided  a  lamp  will  still  burn.  As 
ordinary  black  damp  is  heavier  than  air,  it  was  formerly  identi- 
fied with  CO2.  Its  true  composition  was  first  ascertained  in  1895 
by  Sir  William  Atkinson  and  myself.4  It  is  the  residual  gas  of  an 
oxidation  process,  and  thus  consists  of  nitrogen  with  anything  up 
to  about  21  per  cent  of  carbon  dioxide.  It  is  now  evident  that 
black  damp  may  be  formed  by  several  different  oxidation  pro- 
cesses, among  which  oxidation  of  timber,  of  coal,  and  of  iron 
pyrites  (FeS2)  are  the  most  important. 

When  timber  oxidizes  in  the  process  of  decay,  it  gives  off 
nearly  as  much  CO2  as  it  consumes  oxygen.  Hence  the  black  damp 
formed  consists  of  about  80  parts  of  nitrogen  and  20  of  CO2. 
Freshly  broken  coal  also  oxidizes  slowly  for  some  time  at  ordinary 
temperatures,  but  to  a  very  limited  extent.  The  oxidation  process 
is  a  simple  chemical  one  and  not  dependent  on  microorganisms; 
and  extremely  little  CO2  is  formed.  In  the  oxidation  of  pyrites, 
which  is  also  a  simple  chemical  process,  no  CO2  is  directly  formed ; 
the  sulphur  is  oxidized  to  sulphuric  acid,  which  partly  combines 
with  the  iron  to  form  ferrous  and  ferric  sulphates,  but  may  react 
with  calcium  carbonate  to  form  calcium  sulphate,  CO2  being  of 
course  liberated. 

Black  damp  of  one  sort  or  another  is  found  in  practically  all 
mines,  though  in  coal  mines  where  there  is  much  fire  damp  its 

Haldane  and  Atkinson,  Trans.  Instit.  of  Mining  Engineers,  1895. 


3i2  RESPIRATION 

presence  can  often  be  detected  only  by  analysis,  on  account  of  the 
predominance  of  fire  damp.  Occasionally  there  is  so  little  CO2 
present  in  black  damp  that  it  is  lighter  than  air;  or  it  may  be 
lighter  than  air  owing  to  admixed  fire  damp.  I  found  that  the 
black  damp  formed  simply  in  the  oxidation  of  coal  at  ordinary 
temperatures  contains  small  percentages  of  CO,5  but  black  damp 
as  ordinarily  found  in  considerable  concentrations  in  mines  is 
practically  free  from  CO. 

The  action  of  black  damp  on  lamps  and  candles  is  of  much 
practical  importance,  particularly  as  a  miner  trusts  to  his  lamp 
to  warn  him  of  the  presence  of  black  damp  or  fire  damp.  A  flame 
is  extremely  sensitive  to  any  variation  in  the  oxygen  percentage 
in  air.  If  the  oxygen  percentage  is  increased  the  flame  becomes 
brighter  and  hotter,  and  substances  which  are  not  inflammable 
in  ordinary  air  may  then  become  readily  inflammable.  If  the 
oxygen  percentage  is  diminished  the  flame  becomes  dimmer  and 
less  hot,  unless  the  diminution  is  due  to  the  addition  of  an  inflam- 
mable gas  to  the  air.  When  the  oxygen  percentage  is  dimin- 
ished by  the  addition  of  nitrogen  or  black  damp  to  the  air,  the 
light  given  by  a  candle  or  lamp  diminishes  by  about  3.5  per  cent 
for  a  fall  of  o.i  per  cent  in  the  oxygen  percentage.6  With  a  fall 
of  about  3  to  3.5  per  cent  in  the  oxygen  an  oil  or  candle  flame  is 
extinguished.  Aqueous  vapor  is  even  more  effective  than  nitrogen 
in  causing  extinction  of  flame.  It  should  be  noted  that  it  is  to  the 
percentage,  and  not  the  partial  pressure,  of  oxygen  that  the  flame 
is  so  sensitive,  whereas  it  is  the  partial  pressure  that  is  of  physio- 
logical importance.  A  fall  in  the  oxygen  percentage  of  3  per  cent 
is  of  very  little  importance  to  a  man,  though  it  extinguishes  a 
flame.  On  the  other  hand  a  flame  still  burns  well  when  the  atmos- 
pheric pressure  is  diminished  to  a  third,  while  a  man  is  soon  as- 
phyxiated. Gas  flames  may  be  much  less  readily  extinguished  by 
fall  in  oxygen  percentage  than  oil  or  candle  flames.  Thus  a  hydro- 
gen flame  may  not  be  extinguished  till  the  oxygen  percentage 
falls  to  half  or  even  less,  the  extinction  point  depending  to  a  con- 
siderable extent  on  the  velocity  with  which  the  gas  is  issuing  from 
the  burner.  An  acetylene  lamp  will  burn  till  the  oxygen  percentage 
falls  to  about  12. 

The  physiological  action  of  black  damp  added  to  air  depends 
within  wide  limits  on  the  percentage  of  CO2  in  the  black  damp, 

*  Haldane  and  Meachem,  Trans,  Inst.  of  Mining  Engineers,  1899. 
8  Haldane  and  Llewellyn,    Trans.  Inst.   of  Mining  Engineers,   XLIV,  p.   267, 
1902. 


RESPIRATION  313 

and  can  be  deduced  from  the  data  already  given  as  to  the  physio- 
logical actions  of  CO2  and  oxygen.  It  should  be  noted  that  the 
CO2  diminishes  greatly  the  risk  that  would  otherwise  exist  from 
diminution  of  the  oxygen  percentage.  This  risk  is  greatly  di- 
minished, owing  to  the  fact  that  the  CO2  firstly  increases  the  oxy- 
gen percentage  in  the  alveolar  air  by  stimulating  the  breathing, 
and  secondly  raises  the  hydrogen  ion  concentration  of  the  blood, 
thus  increasing  the  circulation  rate  and  assisting  the  dissociation 
of  oxyhaemoglobin  in  the  tissue  capillaries.  There  is  therefore 
little  or  no  danger  from  lack  of  oxygen  till  the  oxygen  percentage 
in  the  air  falls  to  6  or  7  per  cent;  but  if  the  oxygen  falls  much 
lower  death  occurs  from  want  of  oxygen.  The  very  evident  effect 
of  the  CO2  on  the  breathing  gives  good  warning  of  the  danger, 
so  that  apart  from  the  ample  warning  given  by  a  lamp  a  man  is 
not  likely  to  go  into  a  dangerous  percentage  of  black  damp  unless 
he  does  so  suddenly,  as  in  descending  a  shaft  or  steep  incline. 

In  former  times  miners  often  worked  in  air  containing  so  much 
black  damp  as  to  put  a  great  strain  on  their  breathing  while  they 
were  at  work.  Air  containing,  say,  3  per  cent  of  CO2  doubles  the 
breathing  during  rest;  but  this  effect  is  scarcely  noticeable  sub- 
jectively. During  work,  however,  the  breathing  is  also  about 
double  what  it  would  otherwise  be,  and  the  lungs  are  thus  strained 
to  the  utmost.  Probably  a  great  deal  of  the  emphysema  from 
which  old  miners  used  to  suffer  was  due  to  this  cause.7 

The  ordinary  fire  damp  of  coal  mines  is,  practically  speaking, 
pure  methane  (CH4).  In  a  very  "fiery"  seam  as  much  as  1,500 
cubic  feet  of  methane  may  be  given  off  per  ton  of  coal  extracted. 
The  methane  is  adsorbed  in  the  coal,8  and  may  come  off  under  a 
pressure  of  30  atmospheres  or  more.  Of  other  higher  hydro- 
carbons a  small  amount  is  also  adsorbed  in  the  coal,  but  held  more 
firmly,  so  that  only  in  the  last  fractions  of  gas  coming  off  from 
coal  can  their  presence  be  clearly  demonstrated  by  analysis. 
No  carbon  monoxide  comes  off  with  the  methane,  but  appreciable 
quantities  of  CO2  and  nitrogen  are  often  given  off.  It  occasionally 
happens,  however,  that  enormous  quantities  of  CO2  are  adsorbed 
in  coal  and  may  come  off  in  very  dangerous  outbursts.  This  is  un- 
known in  British  and  American  coal  fields,  but  has  been  met  with 
in  France.  Sudden  outbursts  of  adsorbed  gas,  whether  methane 
or  CO2,  can  only  occur,  however,  where  coal  has  been  locally  dis- 
integrated, as  is  apt  to  be  the  case  near  a  fault.  Ordinary  solid  coal 

*  Haldane,  Trans.  Inst.  of  Mining  Engineers,  LI,  p.  469,  1916. 
8  Graham,  Trans.  Inst.  of  Mining  Engineers,  LII,  p.  338,  1916. 


314  RESPIRATION 

is  so  impermeable  to  gas  that  it  only  adsorbs  or  gives  off  gas 
very  slowly.  In  the  inflammable  gas  associated  with  oil  fields 
higher  hydrocarbons  are  present  in  considerable  amount,  so  that 
the  gas  may  burn  with  a  luminous  flame  and  has  toxic  properties. 
Methane  may  of  course  also  be  produced  by  the  action  of  bacteria 
on  old  timber  or  other  organic  matter  in  the  absence  of  oxygen ; 
and  accidents  from  the  explosion  of  gas  from  this  source  have 
occasionally  occurred  in  British  ironstone  mines. 

When  about  6  per  cent  of  methane  is  present  in  air,  the  mixture 
becomes  inflammable  with  an  ordinary  light,  and  explodes  vio- 
lently with  a  somewhat  higher  percentage.  Curiously  enough, 
however,  an  excess  of  methane  prevents  explosion,  although  plenty 
of  oxygen  is  still  present;  and  with  more  than  about  12  per  cent 


10 

I) 
• 
»< 

• 


/% 


Figure  74. 

Diagram  showing  outlines  of  caps  visible  on  an  oil  flame  with  different 
percentage  of  methane. 

of  methane  the  mixture  ceases  to  be  inflammable.  This  fact  limits 
considerably  the  direct  dangers  from  explosions  of  fire  damp. 

The  presence  of  nonexplosive  proportions  of  fire  damp  in  air 
can  easily  be  detected  by  the  appearance  of  a  "cap"  on  the  flame 
of  a  lamp.  The  cap  is  a  pale,  nonluminous  flame  which  appears  on 
the  top  of  the  ordinary  flame.  In  order  to  see  it  properly  the  ordi- 
nary flame  must  be  either  effectively  shaded  or  lowered  till  little 
else  than  a  blue  flame  is  present,  as  otherwise  the  light  from  the 
ordinary  flame  produces  a  dazzling  effect  which  renders  the  cap 
invisible,  though  it  can  be  photographed  without  difficulty.  The 
length  of  the  cap  depends  on  the  temperature  and  size  of  the 
flame,  and  with  the  very  hot  hydrogen  flame  the  test  becomes  far 
more  delicate,  so  that  as  little  as  0.2  per  cent  of  methane  can  be 
detected  easily.  Figure  74  shows  the  outlines  of  the  cap  visible 


RESPIRATION  315 

with  different  percentages  of  methane  when  an  ordinary  oil  flame 
is  lowered  to  the  extent  required  in  testing. 

To  obviate  the  danger  arising  from  ignition  of  fire  damp  mix- 
tures by  lamps,  some  sort  of  safety  lamp  is  now  always  used  in 
fiery  mines.  A  safety  lamp  may  be  either  an  oil  lamp  constructed 
on  the  general  principle  introduced  by  Davy,  or  an  electric  lamp ; 
but  the  latter  has  of  course  the  disadvantage  that  it  does  not  indi- 
cate the  presence  of  fire  damp  and  black  damp. 

As  regards  its  physiological  properties,  fire  damp  behaves  as 
an  indifferent  gas  like  nitrogen  or  hydrogen.  A  mixture  of  79  per 
cent  of  methane  and  21  of  oxygen  has  the  same  physiological 
properties  as  air,  except  that  the  voice  is  altered ;  and  the  physio- 
logical action  of  methane  is  simply  due  to  the  reduction  which  it 
causes  in  the  oxygen  percentage.  Its  action  can  thus  be  deduced 
from  the  data  in  Chapters  VI  and  VII.  In  actual  practice  the 
danger  from  asphyxiation  by  fire  damp  is  considerably  greater 
than  from  black  damp,  since  a  man  going  with  an  electric  lamp  or 
no  lamp  into  air  progressively  vitiated  by  fire  damp  has  little 
physiological  warning  of  impending  danger.  He  is  in  a  similar 
position  to  an  airman  at  a  very  high  altitude,  and  if  he  suddenly 
falls  from  want  of  oxygen  he  is  very  likely  to  die  from  failure  of 
the  respiratory  center. 

Afterdamp.  Afterdamp  is  the  gas  produced  as  the  result  of  an 
explosion,  and  has  been  known  for  long  to  be  specially  dangerous. 
In  1895  I  made  an  inquiry  into  the  causes  of  death  in  colliery 
explosions,9  and  found  that  nearly  all  (about  95  per  cent)  of  the 
men  who  died  underground  were  killed  by  CO,  although  a  con- 
siderable number  had  received  such  serious  skin  burns  that  they 
could  hardly  have  survived  in  any  case.  Death  was  never  due  to 
deficiency  in  the  oxygen  percentage  of  the  air,  nor  to  excess  of 
CO2,  nor,  apart  from  exceptional  cases,  to  more  than  2  per  cent 
of  carbon  monoxide.  It  was  clear  that  the  men  had  died  in  air 
containing  plenty  of  oxygen,  and  not  much  carbon  monoxide. 
That  carbon  monoxide  was  the  actual  cause  of  death  was  clear 
from  the  fact  that  the  venous  blood  was  usually  about  80  per  cent 
saturated  with  CO ;  and  that  death  was  slow,  and  therefore  due  to 
a  low  percentage  of  CO,  follows  from  the  fact  that  about  the  same 
saturation  was  found  all  over  the  body.  With  more  than  about 
2  per  cent  of  CO  the  venous  blood  has  not  time  to  become  evenly 
saturated  and  the  saturation  is  usually  a  good  deal  lower. 

9  Haldane,  Report  on  the  Causes  of  Death  in  Colliery  Explosions  and  Fires. 
Parl.  Paper  C,  8112,  1896. 


316  RESPIRATION 

Colliery  explosions  were  formerly  attributed  simply  to  ex- 
plosions of  fire  damp.  About  40  years  ago  it  was  first  clearly 
pointed  out  by  Mr.  Galloway  that  this  explanation  is  unsatis- 
factory, and  that  the  spread  of  an  explosion  must  be  due  to  coal 
dust.  Further  evidence  of  the  predominant  part  played  by  coal 
dust  in  all  great  colliery  explosions  was  soon  brought  forward; 
and  it  became  clear  that  many  explosions  occur  in  the  complete 
absence  of  fire  damp,  the  coal  dust  being  originally  stirred  up  and 
lighted  by  the  blowing  out  of  flame  in  blasting,  and  the  explosion 
carried  on  indefinitely  by  further  stirring  up  and  ignition.  In  other 
cases  the  starting  point  is  some,  perhaps  quite  small,  explosion  of 
fire  damp,  caused  by  a  defective  lamp,  a  spontaneous  fire  in  the 
coal,  or  perhaps  even  by  a  spark  from  falling  stone.  The  ease  with 
which  coal  dust  explosions  may  be  produced  by  blasting  when 
even  a  very  little  coal  dust  is  lying  on  a  road,  and  the  astounding 
violence  which  they  may  develop  after  the  flame  has  traveled 
about  a  hundred  yards,  were  strikingly  shown  in  experiments 
made  with  pure  coal  dust  at  Altofts  Colliery  under  Sir  William 
Garforth's  direction.10  On  account  of  their  danger  in  a  populous 
neighborhood  these  experiments  were  transferred  to  Eskmeals  on 
the  Cumberland  coast;  and  finally  showed  that  when  an  equal 
weight  of  shale  dust  or  other  similar  material  was  present  along 
with  the  stone  dust  the  mixture  could  not  be  ignited  by  blasting 
or  gas  explosions.11 

Sir  William  Garforth's  plan  of  stone-dusting  all  the  roads  in 
collieries  with  shale  dust,  so  that  at  no  point  is  there  more  than 
half  as  much  coal  dust  as  shale  dust,  has  now  been  adopted  very 
generally  in  Great  Britain ;  and  the  only  serious  recent  explosions 
have  been  in  mines  where  this  precaution  was  not  adopted.  Stone- 
dusting  is  far  more  efficacious  and  cheaper  than  watering  the 
dust;  and  indeed  efficient  watering  is  impossible  in  many  cases, 
owing  to  the  effect  of  water  on  the  roof  and  sides  of  a  colliery 
road. 

In  the  Altofts  experiments,  samples  of  afterdamp  were  analyzed 
by  Dr.  Wheeler.  The  following  is  a  typical  example. 

Carbon  dioxide  11.9 

Carbon  monoxide  8.6 

Hydrogen  2.9 

Methane  3.1 

Nitrogen  73.5 

10  Record  of  British  Coal-dust  Experiments,  1910. 

11  Reports  of  the  Explosions  in  Mines  Committee,  Parl.  Papers,  1912-1914. 


RESPIRATION  317 

It  will  thus  be  seen  that  pure  afterdamp,  free  from  air,  may 
contain  as  much  as  8.6  per  cent  of  CO.  Fresh  afterdamp  also  con 
tains  an  appreciable  percentage  of  H2S  (not  shown  in  the  analy- 
sis). This  is  a  very  poisonous  gas,  and  o.i  per  cent  will  knock  a 
man  over  unconscious  in  a  very  short  time.  The  most  immediate 
effect  of  fresh  afterdamp  may  be  due  to  H2S ;  but  on  this  point 
there  is  no  definite  knowledge  as  yet. 

Considering  the  deadly  composition  of  pure  afterdamp  it  is  at 
first  sight  somewhat  surprising  that  in  actual  colliery  explosions 
the  men  are  not  killed  at  once  by  the  afterdamp,  and  that  the  CO 
is  so  dilute  in  the  atmosphere  that  kills  them.  It  must,  however, 
be  borne  in  mind  that  along  the  roads  of  collieries  the  coal  dust 
is  never  pure,  and  often  contains  so  much  shale  dust  that  an  ex- 
plosion is  not  possible.  The  combustion  is  probably,  therefore,  far 
from  complete,  so  that  much  air  is  left,  apart  from  what  is  drawn 
in  as  soon  as  the  air  cools.  Possibly,  also,  the  percentage  of  CO  in 
the  pure  afterdamp  is  lower. 

Afterdamp  is,  of  course,  extremely  dangerous  to  rescuers,  and 
many  lives  of  rescuers  have  been  lost  owing  to  poisoning  by  CO. 
They  have  gone  too  far  into  the  poisonous  air  before  becoming 
aware  of  any  danger,  and  the  first  symptom  noticed  is  usually 
faintness  and  failure  of  the  legs,  so  that  return  is  impossible. 
Moreover  the  mental  condition  of  men  beginning  to  be  affected 
by  CO  is  usually  such,  as  already  explained  in  Chapter  VI,  that 
they  will  not  turn  back,  and  are  reckless  of  danger.  A  lamp  is  of 
course  useless  for  indicating  the  danger. 

In  order  to  give  miners  a  practical  means  of  detecting  danger- 
ous percentages  of  CO,  I  introduced  the  plan  of  making  use  of 
a  small  warm-blooded  animal  such  as  a  mouse  or  small  bird.12 
Owing  to  their  very  rapid  general  metabolism  and  respiration  and 
circulation  small  animals  absorb  CO  far  more  rapidly  than  men. 
Hence  they  show  the  effects  of  CO  far  more  quickly,  and  can  thus 
be  used  as  indicators  of  danger,  although  in  the  long  run  they  are 
possibly  rather  less  sensitive  to  CO  than  men  are.  Thus  a  danger- 
ous percentage  which  would  require  nearly  an  hour  to  affect  a  man 
at  rest  will  affect  the  bird  or  mouse  within  about  five  minutes. 
This  test  has  now  come  into  very  general  use,  and  was,  for  in- 
stance, largely  used  during  the  war  by  the  tunneling  companies. 
It  is  easier  to  see  the  signs  of  CO  poisoning  in  a  bird  in  a  small 
cage,  as  it  becomes  unsteady  on  its  perch,  and  finally  drops,  while 
a  mouse  only  becomes  more  and  more  sluggish;  but  the  mouse  is 

"Haldane,  Journ.  of  Physiol.,  XVIII,  p.  448,   1895. 


318  RESPIRATION 

easier  to  handle,  and  less  apt  to  die  suddenly  and  thus  leave  the 
miner  without  any  test.  The  animals  recover  very  quickly  as  soon 
as  purer  air  is  reached  and  this  greatly  increases  their  value  as  a 
test. 

After  an  explosion  it  is  very  necessary  to  have  some  test  for 
CO.  The  ventilation  system  is  thrown  out  of  action  owing  to  doors 
and  air  crossings  being  blown  in.  On  the  other  hand  it  is  very  im- 
portant to  get  in  as  soon  as  possible  in  case  men  are  still  alive,  and 
in  order  to  deal  with  any  smoldering  fires  left  by  the  explosion. 

When  air  in  a  mine  is  for  any  reason  not  safe  to  breathe,  self- 
contained  breathing  apparatus  are  now  frequently  employed.  It 
is  beyond  the  scope  of  this  book  to  describe  these  apparatus  in 
detail  ;13  but  it  may  be  mentioned  that  the  usual  principle  employed 
is  that  the  wearer  breathes  through  a  mouthpiece  into  and  out  of 
a  bag,  the  nose  being  closed  by  a  noseclip.  Into  the  bag  there  is 
directed  a  stream  of  oxygen  from  a  steel  cylinder  carried  behind ; 
and  by  means  of  a  reducing  valve  and  properly  adjusted  opening 
beyond  it  the  stream  is  kept  steady  at  not  less  than  2  liters 
per  minute.  This  is  as  much  as  a  man  uses  during  pretty  hard 
exertion.  If  he  uses  less,  the  excess  is  allowed  to  blow  off. 
If  he  uses  more,  the  oxygen  percentage  in  the  bag  may  fall 
rather  low,  or  the  bag  may  become  flat  before  the  end  of  a  full 
inspiration.  In  the  former  case  he  will  begin  to  pant  more  than 
usual,  but  will  not  fall  over  so  long  as  the  2  liters  are  coming  in. 
If  less  than  about  2  liters  are  coming  in  he  will  be  liable  to  fall 
over,  owing  to  a  rapid  fall  in  the  oxygen  percentage.  If  the  bag 
begins  to  go  flat  he  will  notice  this,  and  either  turn  on  more  oxy- 
gen through  a  by-pass,  or  exert  himself  less.  The  carbon  dioxide 
in  the  expired  air  is  absorbed  by  a  purifier  containing  caustic 
alkali. 

In  another  form  of  apparatus  the  delivery  of  oxygen  is  gov- 
erned by  the  state  of  fullness  of  the  bag;  but  in  applying  this 
principle  there  is  the  difficulty  that  the  oxygen  may  not  be  quite 
pure,  and  the  contained  nitrogen  may  thus  accumulate  in  the  bag, 
or  a  little  nitrogen  may  leak  in  from  the  air  at  the  mouthpiece. 

In  still  another  form  use  is  made  of  liquid  air,  of  which  a  large 
amount  can  be  carried,  so  that  most  of  the  expired  CO2  can  be 
allowed  to  pass  out  and  only  a  small  purifier  is  needed. 

13  A  thorough  discussion  of  the  apparatus  in  use  in  America  and  the  principles 
and  practice  applicable  to  it  is  given  in  U .  S.  Bureau  of  Mines  Technical  Paper, 
No.  82,  1917,  by  Yandell  Henderson  and  J.  W.  Paul.  Numerous  investigations, 
including  two  full  reports  by  myself,  have  appeared  in  Great  Britain. 


RESPIRATION  319 

Whichever  form  of  apparatus  is  used  it  is  very  necessary  that 
it  should  be  extremely  reliable  in  its  action,  and  that  the  users 
should  be  thoroughly  instructed  and  trained  in  its  proper  use  and 
upkeep.  A  number  of  lives  have  been  lost  or  endangered  through 
defective  supervision  and  mode  of  use,  or  defective  design,  of 
apparatus;  and  as  a  consequence  of  these  defects  men  wearing 
the  apparatus  in  quite  breathable  air  have  often  had  to  be  rescued 
by  men  without  apparatus.  With  proper  and  scientific  supervision 
these  accidents  do  not  occur,  as  has  been  shown  again  and  again 
during  extensive  operations  in  irrespirable  air. 

By  white  damp  miners  understand  a  poisonous  form  of  gas 
coming  off  from  coal  which  has  spontaneously  heated.  The  term 
seems  to  have  arisen  from  the  fact  that  steam  commonly  comes 
off  from  the  warm  coal  with  this  poisonous  gas  and  causes  a  white 
mist.  By  experiments  on  animals  and  analyses  I  have  frequently 
found  that  the  poisonous  constituent  of  the  gas  was  CO. 

Freshly  broken  coal  is,  as  already  mentioned,  liable  to  a  slow 
oxidation  process.  This  of  course  produces  heat,  and  if  sufficient 
coal  is  present,  so  that  the  heat  is  not  lost  as  quickly  as  it  is  pro- 
duced, the  coal  will  heat,  and  the  heated  coal  will  oxidize  faster 
and  faster  until  at  last  it  is  red  hot  or  bursts  into  flame  if  sufficient 
oxygen  is  present.  It  is  for  this  reason  that  coal  may  be  a  danger- 
ous cargo  on  long  voyages,  and  that  coal  cannot  be  stacked  safely 
in  very  high  heaps.  In  many  seams  there  is  great  trouble  and  no 
little  danger  from  spontaneous  heating  of  broken  coal  under- 
ground ;  and  the  residual  gas  coming  off  from  heated  coal  is  often 
called  white  damp.  The  higher  the  temperature  of  coal  which  is 
slowly  oxidizing,  the  greater  the  proportion  of  CO  in  the  residual 
gas.  The  effects  of  white  damp  are  thus  much  the  same  as  those 
of  afterdamp ;  and  the  same  precautions  are  required. 

Smoke  in  mines  may  come  either  from  fires  or  from  blasting. 
The  smoke  from  a  fire  is  usually,  of  course,  visible  and  irritates 
the  air  passages  and  eyes  owing  to  the  irritant  properties  of  the 
suspended  particles.  If,  however,  smoke  has  slowly  traveled  some 
distance  in  a  mine,  the  particles  have  subsided  and  the  smoke  has 
become  a  more  or  less  odorless  and  transparent  gas.  Many  very 
serious  accidents,  involving  sometimes  the  loss  of  100  lives,  have 
occurred  through  the  poisonous  action  of  smoke  from  fires  in 
mines.  In  these  cases  the  deaths  have  always,  so  far  as  hitherto 
ascertained,  been  due  to  CO  poisoning.  A  large  amount  of  un- 
burnt  CO  is  given  off  from  smoky  or  smoldering  fires,  so  that  the 
gases  from  a  fire  are  almost  as  dangerous  as  the  afterdamp  of  an 


320  RESPIRATION 

explosion.  Practically  speaking,  afterdamp  and  smoke  from  fires 
produce  nearly  the  same  effects,  and  require  the  same  precautions. 
A  fire  in  the  main  intake  of  a  mine  is  a  most  dangerous  occurrence, 
since  the  poisonous  gas  is  apt  to  be  carried  all  over  the  mine,  and 
to  kill  all  the  men  in  it.  To  afford  a  means  of  dealing  with  this 
danger,  the  ventilating  fans  provided  at  British  coal  mines  are 
now  so  constructed  that  the  air  current  can  be  at  once  reversed,  so 
as  to  drive  back  the  smoke. 

Smoke  from  blasting  may  contain  various  poisonous  gases, 
along  with  CO2,  according  to  the  nature  of  the  explosive.  Some 
explosives,  such  as  guncotton,  give  much  CO,  and  some  very 
little ;  but  all  seem,  in  practice,  to  give  some.  Hence  there  is  always 
risk  of  CO  poisoning  where  explosives  are  used  in  mines,  unless 
the  proper  precautions  are  taken.  Black  gunpowder,  as  used  for 
blasting,  produces  both  CO  and  H2S ;  and  in  the  cases  of  gassing 
it  is  often  difficult  to  decide  whether  CO  or  H2S  has  been  mainly 
responsible  for  the  effects.  With  explosives  containing  nitro- 
compounds  another  and  very  serious  danger  is  met  with.  When 
these  explosives  detonate  properly  the  nitrogen  is  given  off  as 
nitrogen  gas;  but  when  they  burn  instead  of  detonating,  the 
nitrogen  comes  off  as  nitric  oxide,  along  with  CO  instead  of  CO2. 
In  practice,  owing  to  defective  detonators  or  other  causes,  some 
of  the  explosive  is  apt  to  burn  instead  of  detonating.  The  nitric 
oxide  then  passes  into  the  air  and  combines  with  oxygen  to  form 
yellow  nitrous  fumes.  These  have  a  somewhat  irritant  effect  at  the 
time,  but  this  is  not  sufficient  to  give  proper  warning  of  their 
dangerous  properties.  The  immediate  effects  are  very  slight.  If, 
however,  enough  of  the  mixture  has  been  inhaled,  the  result  is 
that  after  a  few  hours  symptoms  of  very  severe  lung  irritation 
appear,  and  finally  oedema  of  the  lungs  and  great  danger  to  life. 
I  have  found  that  exposure  to  the  fumes  from  as  little  as  .05  per 
cent  of  nitric  oxide  in  air  may  be  fatal  to  an  animal.  This  subject 
will  be  referred  to  more  fully  below  in  connection  with  poisonous 
gas  used  in  war. 

Poisoning  with  CO  in  mines  is  so  apt  to  occur,  that  a  few  words 
may  not  be  out  of  place  as  to  the  treatment  of  CO  poisoning.  The 
symptoms  and  their  cause  have  already  been  dealt  with.  The  first 
thing,  is,  of  course,  to  get  the  patient  out  of  the  poisonous  air.  In 
doing  so,  however,  it  is  important  to  keep  him  well  covered  and 
avoid  in  any  possible  way  exposing  him  to  cold.  For  some  reason 
which  is  at  present  not  clear,  a  man  suffering  from  CO  poisoning 
gets  much  worse  on  exposure  to  cooler  and  moving  air,  as  in  the 


RESPIRATION  321 

main  intake  of  a  mine.  If  the  breathing  has  stopped  artificial  res- 
piration should  be  applied  promptly ;  and  this  can  best  be  done  by 
Schafer's  well-known  method.  If  oxygen  is  available  it  should  be 
given  at  once.  It  immediately  increases  greatly  the  amount  of  dis- 
solved oxygen  in  the  blood,  and  also  expels  far  more  rapidly  the 
CO  from  the  blood,  as  will  be  evident  considering  the  properties 
of  CO  haemoglobin.  The  oxygen  will  do  most  good  at  first,  and 
may  be  continued  with  advantage  for  at  least  twenty  minutes.  Suit- 
able apparatus  for  giving  oxygen  can  now  be  obtained  easily.  Hen- 
derson and  Haggard  have  recently  shown,  however,  that  owing  to 
the  great  washing  out  of  CO2  which  occurs  during  the  hyperpnoea 
produced  in  acute  CO  poisoning,  or  perhaps  owing  to  temporary 
exhaustion  of  the  respiratory  center,  the  breathing  is  apt  to  re- 
main for  some  time  inadequate. 13A  They  found  by  experiments  on 
animals  that  under  this  condition  the  removal  of  CO  from  the 
blood  is  greatly  accelerated  by  adding  CO2  to  the  air  or  oxygen 
inhaled.  The  desirability  of  having  some  safe  and  practicable 
means  of  adding  CO2  to  oxygen  used  in  reviving  men  poisoned  by 
CO  seems  evident  from  these  experiments. 

A  man  who  has  been  badly  gassed  by  CO,  and  has  been  un- 
conscious for  some  time,  is  sure  to  have  very  formidable  symptoms, 
lasting  long  after  all  traces  of  CO  have  disappeared  from  the 
blood.  He  may  never  recover  consciousness  at  all;  but  when  he 
does  his  nervous  system  generally  is  likely  to  remain  very  seriously 
affected  for  days,  weeks,  or  months,  so  that  he  requires  to  be  care- 
fully watched,  nursed,  and  treated.  Mental  powers  and  memory 
may  be  much  impaired,  and  the  nervous  system  seems  to  be  in- 
jured in  many  different  directions.  Thus  the  regulation  of  body 
temperature  is  apt  to  be  imperfect,  and  symptoms  resembling  those 
of  peripheral  neuritis  are  common.  A  condition  of  neurasthenia, 
similar  to  that  so  often  seen  during  the  war,  appears  to  result  fre- 
quently, with  the  usual  affections  of  the  respiratory  and  cardiac 
nervous  system.  In  some  cases  there  seems  to  be  acute  dilatation  of 
the  heart ;  and  probably  almost  every  organ  in  the  body  has  suf- 
fered from  the  effects  of  want  of  oxygen. 

As  mines  grow  deeper  and  warmer,  the  importance  of  the  wet- 
bulb  temperature  in  connection  with  mine  ventilation  becomes 
more  and  more  prominent.  The  reasons  for  this  will  be  evident 
from  what  has  already  been  said  on  this  subject;  especially  when 
the  fact  that  a  miner  has  to  do  hard  physical  work  is  also  taken  into 

13A  Yandell  Henderson  and  Haggard,  Journ.  of  Pharmac.  and  Exper.  Therap., 
XVI,  p.  u,  1920. 


322  RESPIRATION 

consideration.  To  this  subject  I  have  given  very  close  attention 
in  recent  years,  and  a  full  general  discussion  of  it  will  be  found  in 
the  recent  Report  of  the  Committee  on  Control  of  Temperature 
in  Mines.14 

Owing  to  the  nature  of  their  work  and  the  dry  conditions  in 
deep  and  well-ventilated  mines,  miners  are  very  much  exposed 
to  dust  inhalation;  and  the  prevalence  of  "miners'  phthisis" 
among  certain  classes  of  miners  led  me  to  the  investigation  of  the 
effects  of  dust  inhalation.  Both  men  and  animals  are  in  general 
more  or  less  exposed  to  dust  inhalation.  The  problem  presented 
by  dust  inhalation  in  mining  and  other  dusty  occupations  is  thus 
only  a  part  of  a  general  physiological  problem  as  to  how  the  dust 
inhaled  along  with  air  is  dealt  with  by  the  body.  It  is  evident  that 
if  the  insoluble  dust  which  is  constantly  being  inhaled  by  civilized 
men,  particularly  in  towns  and  in  dusty  occupations,  accumulated 
in  the  lung  alveoli,  the  effects  would  in  time  be  disastrous.  There 
is,  however,  no  evidence  that  such  effects  are  ordinarily  produced. 
The  lungs  of  a  town  dweller,  for  instance,  are  more  or  less  black- 
ened by  smoke  particles,  but  remain  perfectly  healthy;  and  the 
same  applies  to  the  lungs  of  coal  miners  and  of  persons  engaged 
in  many  other  very  dusty  occupations.  In  other  cases,  however, 
such  as  certain  kinds  of  metalliferous  mining,  steel  grinding, 
pottery  work,  etc.,  the  effects  of  continuous  inhalation  of  the  dust 
are  disastrous.  Why  have  certain  kinds  of  insoluble  dust  no  cumu- 
lative bad  effect  on  the  lungs?  Why,  on  the  other  hand,  have  other 
kinds  such  disastrous  cumulative  effects?  When  the  first  question 
is  answered  the  second  becomes  relatively  easy. 

It  is  in  the  production  of  phthisis  (pulmonary  tuberculosis) 
that  the  continued  inhalation  of  a  dangerous  variety  of  dust  shows 
its  effects  most  clearly.  The  following  table,  which  I  compiled 
from  the  statistics  of  the  Registrar  General  for  England  and 
Wales,  shows  the  marked  contrast  between  different  occupations 
as  regards  the  effects  of  dust  inhalation  in  producing  phthisis. 
Two  dusty  occupations  are  included — coal  mining  and  tin  mining. 
Of  the  two,  coal  mining  is  much  the  dustier  occupation.  It  will  be 
seen,  however,  that  among  coal  miners  there  is  not  only  very  little 
phthisis,  but  even  less  than  among  farm  workers,  and  much  less 
than  the  average  for  all  other  occupations.  Among  tin  miners,  on 
the  other  hand,  there  is  a  great  excess  of  phthisis;  and  detailed 

14  First  Report  of  the  Committee  on  Control  of  Underground  Temperature, 
Trans.  Inst.  of  Mining  Engineers,  1920. 


RESPIRATION  323 

investigation  has  shown  clearly  that  it  is  to  dust  inhalation  that 
this  excess  is  solely  due.15 

A  very  large  proportion  of  the  dust  in  inspired  air  is  caught  on 
the  sides  of  the  nasal  and  bronchial  inspiratory  passages,  from 
which  it  is  continuously  removed  by  the  action  of  the  ciliated 
epithelium.  It  is  only  the  very  finest  particles  that  penetrate  to  the 
lung  alveoli.  Nevertheless  large  amounts  of  dust  do,  as  a  matter 


DEATH  RATES  FROM  PHTHISIS  PER   1000 

LIVING  AT  EACH 

AGE  PERIOD  FOR  ENGLAND  AND  WALES,  1900-1902 

Age  period 

15-25 

25-35 

35-45 

45-55 

55-65 

All  occupied  and  retired  males 

i.i 

2.1 

2.9 

3-2 

2.6 

coal  miners 

0.7 

1.0 

I.I 

i-5 

2.0 

farm  workers 

0.6 

I.I5 

1-3 

1.4 

2.6 

tin  miners 

0.4 

7.0 

II.7 

16.1 

16.2 

of  fact,  reach  the  alveoli.  Arnold  showed  that  even  what,  in  human 
experience,  is  relatively  harmless  dust,  will  produce,  if  inhaled 
in  very  large  amount,  foci  of  scattered  broncho-pneumonia  in  the 
lungs,  and  that  quartz  dust  is  specially  apt  to  produce  inflam- 
matory changes  followed  by  development  of  connective  tissue.18 
In  connection  with  the  use  of  shale  dust  for  preventing  colliery 
explosions  Beattie  showed  that  neither  coal  dust  nor  shale  dust 
produce  any  harm  in  animals  if  the  dust  is  inhaled  in  the  moder- 
ate quantities  comparable  to  what  a  miner  inhales.  On  the  other 
hand,  the  dust  from  grindstones  produces  signs  of  fibrosis.17  The 
subject  was  followed  further  in  my  laboratory  by  Mavrogardato 
in  an  investigation  undertaken  for  the  Medical  Research  Com- 
mittee.18 This  work  showed  that  the  very  fine  particles  which 
reach  the  alveoli  are  rapidly  taken  up  by  special  cells  of  the  al- 
veolar walls.  When  coal  dust  or  shale  dust  was  inhaled,  these  cells 
soon  detached  themselves  and  wandered  away  with  their  load  of 
dust  particles.  Some  pass  directly  into  the  open  ends  of  the  bron- 
chial tubes,  and  are  thence  swept  upwards  by  the  cilia.  Others 
pass  into  lymphatic  vessels  and  are  carried  to  the  nodules  of  lym- 

15  Haldane,   Martin,   and   Thomas,   Report  on  the  Health  of  Cornish  Miners, 
Parl.  Paper  Cd,  2091,  1904. 

18  Arnold,  Untersuchungen  uber  Staubinhalation  und  Staubmetastase,   1885. 

17  Beattie,  First  Report  of  Explosions  in  Mines  Committee,  Parl.   Paper,   Cd, 
6307.  1912. 

18  Mavrogardato,  Journ.  of  Hygiene,  XVII,  p.  439,  1918. 


324  RESPIRATION 

phatic  tissue  surrounding  bronchi  and  then  pass  right  through 
the  walls  of  the  bronchi  and  are  swept  out.  Others  reach  the 
lymphatic  glands  at  the  roots  of  the  lungs,  and  finally  seem  to  pass 
from  there  into  the  blood.  In  this  way  the  dust  is  removed  from 
the  lungs,  and  if  too  much  dust  is  not  inhaled  the  process  of  re- 
moval will  keep  pace  with  the  introduction  of  dust.  The  well- 
known  "black  spit"  of  a  collier,  which  continues  for  long  periods 
when  he  is  not  working  underground,  is  apparently  a  healthy 
sign  showing  that  dust  particles  are  being  removed  from  the 
lungs.  It  seems  quite  probable,  also,  that  the  efficiency  of  the 
physiological  process  for  dealing  with  dust  improves  with  use, 
like  other  physiological  processes.  Moreover  the  dust-collecting 
cells  appear  to  be  identical  with  cells  which  collect  and  deal 
with  bacteria  in  the  lungs.  Possibly,  therefore,  the  somewhat  re- 
markable immunity  of  colliers  from  phthisis  is  connected  with 
their  capacity  for  dealing  with  inhaled  dust  particles.19 

At  the  end  of  a  few  months  the  lungs  of  a  guinea  pig  which  have 
been  heavily  charged  with  coal  dust  or  shale  dust  by  experimental 
inhalations  are  again  free  from  dust.  On  the  other  hand  this  was 
not  the  case  when  the  dust  inhaled  was  quartz.  Most  of  the  quartz 
remained  in  situ,  though  mainly  within  the  dust-collecting  cells. 
Part  had,  however,  been  carried  onward  to  lymphatic  glands.  The 
quartz  did  not  seem  to  excite  the  cells  to  wander  in  the  same  way 
as  the  coal  dust  or  shale  dust  did ;  and  it  appeared  as  if  this  dif- 
ference in  the  properties  of  different  kinds  of  dust  explained  why 
some  dusts  are  much  more  apt  than  others  to  produce  cumulative 
ill  effects  in  the  lungs.  Presumably  the  quartz  particles  are  so 
inert  physiologically  that  they  do  not  excite  the  dust-collecting 
cells  to  wander  away.  Other  kinds  of  dust  particles  may  be  equally 
insoluble,  but  may  also  be  charged  with  adsorbed  material  which 
makes  them  physiologically  active.  Coal,  for  instance,  though  very 
insoluble  in  water,  adsorbs  substances  of  all  kinds,  and  the  im- 
portance of  its  power  of  adsorbing  gases  has  already  been  pointed 
out. 

Shale  dust  was  found  by  Dr.  Mellor  to  contain  about  35  per 
cent  of  quartz.  Nevertheless  the  quartz  in  shale  dust  does  no  harm 
to  the  lungs  and  is  eliminated  readily.  There  are  many  other 
kinds  of  stone  which  contain  still  more  quartz,  but  also  produce  a 
harmless  dust.  In  fact  nearly  all  the  dust  ordinarily  met  with  is 
of  the  harmless  variety,  and  Mavrogardato's  investigation  indi- 

19  Haldane,  Trans.  Inst.  of  Mining  Engineers,  LV,  p.  264,  1918. 


RESPIRATION  325 

cated  that  quartz  dust  becomes  relatively  harmless  when  it  is 
mixed  with  other  dust  of  the  harmless  variety.  The  lung  cells 
appear  to  clear  out  the  quartz  when  they  are  clearing  out  the  other 
dust. 

It  is  evident  that  much  further  investigation  is  needed  in  order 
to  elucidate  completely  the  physiology  of  dust  excretion  from  the 
lungs.  It  is  equally  evident,  however,  that  this  process  is  under 
physiological  control,  just  as  much  as  other  physiological  activi- 
ties are. 

Air  of  Wells.  The  case  of  the  air  of  wells  and  other  unventilated 
underground  spaces  differs  from  that  of  mines  owing  to  the  fact 
that  no  artificial  ventilation  is  provided  for.  It  might  be  supposed 
that  the  air  in  a  well,  with  only  rock  or  brickwork  round  it,  pure 
water  at  the  bottom,  and  the  top  more  or  less  open,  would  never 
be  more  than  slightly  contaminated.  Experience  shows,  however, 
that  this  is  not  the  case,  and  that  the  air  in  even  a  shallow  well, 
only  a  few  feet  deep,  is  sometimes  dangerously  contaminated. 
In  1896  I  investigated  this  subject,  visiting  various  wells  where 
men  had  been  asphyxiated,  in  order  to  see  what  had  happened.20 
I  found  plenty  of  foul  air,  and  that  its  composition  was  similar 
to  that  of  black  damp,  and  not  simply  CO2,  as  was  then  believed. 
The  composition  of  the  gas  varied  from  about  80  per  cent  nitro- 
gen and  20  per  cent  CO2  to  almost  pure  nitrogen ;  and  it  was  quite 
evident  that  this  black  damp  or  choke  damp  was  simply  the 
residual  gas  from  oxidation  processes  occurring  in  the  strata 
round  the  well. 

Another  point  which  emerged  quite  clearly  was  that  the  state 
of  the  air  in  any  well  liable  to  foul  air  depended  entirely  on 
changes  in  barometric  pressure.  With  a  rising  barometer  the  air 
was  quite  clear,  and  with  a  falling  barometer  it  was  foul.  Thus 
any  fall  in  barometric  pressure  might  make  a  well  very  dangerous, 
though  an  hour  before  the  air  was  quite  pure.  Moreover  with  a 
falling  barometer  the  well  might  be  brimful  and  rapidly  over- 
flowing with  dangerous  gas.  The  danger  to  which  well  sinkers 
are  exposed  is  thus  evident  At  one  well  an  engine  house  which 
covered  the  top  of  the  well  had  been  built,  and  sometimes  it  was 
unsafe  to  enter  this  building  owing  to  the  gas,  unless  doors  and 
windows  were  wide  open.  The  engine  man  was  much  comforted 
when  I  lent  him  an  aneroid  barometer  and  thus  convinced  him  that 
the  outbursts  of  gas  were  due  to  natural  and  not  supernatural 

20  Haldane,  Trans.  Inst.  of  Mining  Engineers,  1896. 


326  RESPIRATION 

causes.  By  always  carrying  a  lighted  candle  or  lamp  with  him,  a 
well  sinker  can  guard  most  effectually  against  the  danger  from 
black  damp ;  but  it  is  quite  unsafe  to  trust  to  previous  tests. 

It  is  thus  evident  that  a  well  acts  as  a  chimney  communicating 
with  a  large  air  space  in  the  substance  of  the  surrounding  rock, 
or  in  crevices  within  it.  Air  may  either  be  going  down  this  chim- 
ney or  returning;  and  if  the  rock  contains  any  oxidizable  material 
such,  for  instance,  as  iron  pyrites,  the  returning  air  or  gas  has 
lost  more  or  less  of  its  oxygen,  and  possibly  also  gained  some  CO2. 
If,  however,  less  than  about  4  per  cent  of  CO2  were  present  in 
the  black  damp  it  would  be  lighter  than  air,  and  thus  likely  to 
escape  unnoticed. 

An  interesting  case  which  came  under  my  notice  later  may  be 
mentioned  in  this  connection.  While  a  tunnel  was  being  driven  with 
compressed  air  under  the  Thames  it  was  found  that  in  a  large 
cold  storage  on  the  river  bank  lamps  or  candles  were  extinguished. 
The  air  was  analyzed  for  CO2,  but  no  noticeable  excess  was  found. 
On  analysis  I  found  the  air  very  poor  in  oxygen.  On  further 
investigation  it  turned  out  that  air  very  poor  in  oxygen,  but  with 
practically  no  excess  of  CO2,  was  coming  up  the  shaft  of  a  well 
belonging  to  the  building.21  The  flow  did  not  depend  on  baro- 
metric pressure,  and  nothing  of  the  sort  had  occurred  before  the 
construction  of  the  tunnel  began.  It  was  evident,  therefore,  that 
the  flow  was  due  to  compressed  air  escaping  deep  down  through 
the  London  clay  from  the  advancing  end  of  the  tunnel,  and 
forcing  a  way  to  the  well,  but  at  the  same  time  losing  oxygen 
owing  to  the  presence  in  the  clay  of  oxidizable  material  such  as 
iron  pyrites.  The  pure  black  damp  contained  99.6  per  cent  of 
nitrogen  and  0.4  per  cent  of  CO2. 

Air  of  Railway  Tunnels.  Although  the  great  difficulties  form- 
erly experienced  in  the  ventilation  of  long  railway  tunnels  have 
been  overcome  by  the  substitution  of  electric  traction  for  steam 
locomotives,  it  may  be  worth  while  to  record  here  some  of  these 
difficulties.  Probably  the  worst  cases  were  those  of  single-line 
tunnels  on  a  stiff  gradient  in  the  Apennines.  When  the  wind  was 
blowing  in  the  same  direction  as  a  train  was  traveling  on  an  up- 
gradient  the  smoke  from  the  engine  or  engines  tended  to  travel 
with  the  train.  Thus  the  air  rapidly  became  poisonous  from  the 
presence  of  CO,  and  the  oxygen  percentage  fell  so  low  that  some- 
times lights  were  extinguished  and  steam  began  to  fail,  owing 

21  Blount,  Journ.  of  Hygiene,  VI,  p.  175,  1906. 


RESPIRATION  327 

to  the  engine  fires  burning  badly.  The  passengers  could  partly 
protect  themselves  by  closing  the  windows;  but  the  engine  drivers 
were  liable  to  become  unconscious,  and  at  least  one  very  serious 
accident  occurred,  owing  to  a  train  running  on  with  the  men  on  the 
engine  unconscious. 

In  the  London  Underground  Railway  there  was  also  much 
trouble,  owing  to  the  great  traffic,  although  there  were  numerous 
openings  to  the  street  along  all  parts  of  the  system,  and  a  colliery 
fan  had  also  been  installed  at  one  point.  The  difficulties  were 
referred  to  a  Board  of  Trade  Committee  of  which  I  was  a  member, 
and  I  made  numerous  analyses  of  the  air.22  It  was  never  so  bad 
as  appeared  to  have  been  sometimes  the  case  in  the  Apennine  tun- 
nels, and  the  trouble  from  sulphuric  acid  and  smoke  was  largely 
mitigated  by  the  use  of  Welsh  steam  coal  containing  very  little  sul- 
phur. The  air  was  often,  however,  very  unpleasant,  and  many 
persons  were  unable  to  use  the  railway.  At  busy  times  the  per- 
centage of  CO2  might  rise  as  high  as  0.8,  and  of  CO  to  .06 ;  but  of 
course  passengers  and  railwaymen  were  not  long  enough  exposed 
to  this  air  to  suffer  from  the  effects  of  CO,  and  repairing  work  on 
the  line  was  not  carried  out  except  at  night.  At  the  end  of  the 
inquiry  it  was  agreed  to  introduce  electric  traction,  and  since  this 
was  done  there  has  been  no  further  difficulty.  The  tunnels  are  close 
to  the  surface,  and  the  trains  push  abundance  of  air  out  and  in 
through  openings  to  the  outside  air. 

In  the  (London)  tubes,  which  lie  much  deeper,  the  ventilating 
action  of  the  trains  proved  insufficient  by  itself  to  prevent  the  air 
from  becoming  rather  unpleasant;  and  systematic  ventilation  by 
fans  was  therefore  adopted.  In  various  other  railway  tunnels 
simple  shafts  are  provided;  and  in  the  Severn  Tunnel  there  is  a 
nearly  central  shaft  provided  with  a  powerful  fan.  By  these 
means  the  air  is  kept  fairly  pure. 

Air  of  Sewers.  The  air  of  sewers  is  perhaps  mainly  of  interest 
in  connection  with  the  time-honored  belief  that  "sewer  gas" 
spreads  infection.  Some  of  my  earliest  scientific  work  was  con- 
cerned with  the  air  commonly  present  in  sewers,  and  was  started 
by  the  late  Professor  Carnelley  and  myself23  at  the  request  of  a 
House  of  Commons'  Committee  appointed  in  consequence  of  alarm 
as  to  the  sewers  of  the  House  of  Commons. 

The  air  of  a  sewer  has,  of  course,  an  unpleasant  smell,  which, 
however,  is  hardly  noticed  except  at  the  manhole  by  which  access 

M  Report  of  the  Committee  on  Tunnel  Ventilation,  Parl.  Paper,  1897,  Appendix  i. 
a3  Carnelley  and  Haldane,  Proc.  Roy.  Soc.,  4-?,  p.  501,  1887. 


328  RESPIRATION 

is  gained  to  the  sewer.  The  air  is  saturated  with  moisture,  and 
may  be  somewhat  warm  if  much  warm  water  flows  into  the  sewer. 
Chemically  speaking,  however,  the  air  is  very  little  contaminated. 
Even  in  the  sewers  of  Bristol,  where  ventilating  shafts  were  re- 
duced to  a  minimum,  I  found  only  about  0.2  per  cent  of  CO2.  On 
determining  the  number  of  bacteria  in  the  air  we  found  that 
fewer  were  present  in  the  sewer  air  than  outside,  but  of  much  the 
same  kinds.  In  sewers  which  were  well  ventilated  there  were  far 
more  than  in  badly  ventilated  sewers;  and  it  was  evident  that 
nearly  all  the  bacteria  came  from  the  outside  through  the  venti- 
lators. Where  there  was  much  splashing,  however,  a  few  were 
thrown  into  the  air.  These  results,  which  have  been  confirmed  by 
other  investigators,  are  just  what  might  be  expected.  Particulate 
matter  is  not  given  off  from  moist  surfaces  apart  from  mechani- 
cally acting  causes,  and  any  bacteria  or  other  particles  driven 
into  suspension  in  the  air  of  a  sewer  will  tend  to  fall  back  again. 
It  is  conceivable  that  infection  might  be  carried  by  sewer  air ;  but 
innumerable  other  paths  of  infection  are  much  more  probable. 

Although  ordinary  sewer  air  is  chemically  very  pure,  and  not 
even  a  trace  of  H2S  can  be  found,  accidents  to  sewermen  from 
foul  air  are  not  very  uncommon ;  and  there  is  no  doubt  that  most 
of  these  accidents  are  due  to  H2S.  I  investigated  one  case  of  this 
kind  where  five  men  had  lost  their  lives  at  a  manhole — the  last 
four  in  attempts  at  rescue.24  All  the  symptoms  described,  includ- 
ing irritation  of  the  eyes,  were  those  of  H2S  poisoning ;  and  though 
the  air  was  not  poisonous  when  I  descended,  a  little  H2S  was 
present.  When  some  of  the  sewage  was  put  into  a  large  bottle  and 
shaken  up,  H2S  was  found  to  be  present,  and  a  mouse  lowered 
into  the  bottle  showed  severe  symptoms  of  H2S  poisoning.  These 
symptoms  were  absent  when  lead  acetate  was  added  before  shak- 
ing, or  when  caustic  soda  was  added. 

It  is  only  when  sewage  stagnates  or  deposits  solid  matter  that 
H2S  is  formed.  Any  cause  that  stirs  this  sewage,  or  liberates  H2S 
from  it,  may  make  the  air  dangerous.  About  0.2  per  cent  will  kill 
an  animal  within  a  minute  or  two ;  and  o.  I  per  cent  will  rapidly 
disable  it.  H2S  is  thus  a  good  deal  more  poisonous  than  CO,  and 
far  quicker  in  its  action. 

Another  source  of  danger  is  lighting  gas  from  leaky  street 
mains.  Lighting  gas  is  frequently  met  with  in  sewers,  and  I  have 
several  times  smelt  it  in  sewers.  In  one  recent  case  which  I  in- 
vestigated two  men  were  killed  by  CO  poisoning  from  lighting 

*'  Lancet,  Jan.  25,  1896. 


RESPIRATION  329 

gas.  There  seems  to  be  no  evidence  of  accidents  in  sewers  from  any 
other  gas  than  H2S  or  CO ;  but  many  strange  smells  are  en- 
countered, and  we  were  once  much  alarmed  by  chlorine  coming 
from  a  bleaching  factory. 

Air  of  Ships.  In  the  compartments  of  a  ship  air  is  specially 
liable  to  become  foul  owing  to  the  air-tight  conditions  which 
often  exist.  In  a  double  bottom  compartment,  for  instance,  the 
whole  of  the  oxygen  may  disappear,  owing  to  rusting  or  to  ab- 
sorption of  oxygen  by  drying  paint.  In  an  ordinary  compartment 
battened  down  the  same  thing  may  also  occur  owing  to  slow  ab- 
sorption of  oxygen  by  articles  of  cargo,  such  as  grain,  wool,  etc. 
Accidents  from  this  cause  are  not  infrequent  if  men  descend  with- 
out first  testing  the  air  with  a  lamp  or  giving  time  for  ventilation 
to  occur.  In  coal  bunkers  fire  damp  may  accumulate  in  the  absence 
of  proper  ventilation,  or  else  the  oxygen  may  fall  very  low.  Coal 
trimmers  are  occasionally  also  affected  by  what  appears  to  be  CO 
poisoning  due  to  small  quantities  of  CO  formed  at  ordinary 
temperatures  in  the  slow  oxidation  of  coal,  as  described  above. 

The  ventilation  of  passenger  and  crew  spaces  on  ships  was  very 
defective,  particularly  in  rough  weather,  until  fan  ventilation  was 
generally  introduced.  It  was  forgotten  that  the  rooms  in  a  ship 
do  not  ventilate  themselves  naturally  through  walls  and  roof,  as 
a  house  ashore  does.  Owing  to  the  close  quarters,  it  is  often  diffi- 
cult to  ventilate  the  spaces  in  a  ship  properly  without  causing 
intolerable  draughts.  In  the  mess  decks  of  warships  this  is  specially 
difficult,  as  there  are  hammocks  everywhere  at  night.  The  matter 
was  investigated  recently  by  an  Admiralty  Committee  of  which 
I  was  a  member  and  a  system  introduced  by  which  equal  amounts 
of  air  can  be  made  to  issue  from  a  large  number  of  louvres  on  the 
sides  of  ventilating  ducts.  In  this  way  the  men  are  supplied  with 
an  average  of  50  cubic  feet  of  air  each  per  minute,  without  any 
unpleasant  draught  impinging  on  any  one.  The  temperature,  and 
particularly  the  wet-bulb  temperature  in  warm  weather,  can  also 
be  controlled  very  efficiently  by  this  plan.  With  men  perspiring 
more  or  less  from  heat,  and  giving  off  perhaps  fifty  times  as  great 
a  volume  of  aqueous  vapor  as  of  CO2,  very  ample  artificial  venti- 
lation is  needed  when  no  other  means  of  ventilation  is  available. 

Gas  Warfare.  It  would  be  out  of  place  to  attempt  to  discuss  the 
nature  and  mode  of  action  of  the  various  substances  used  in  gas 
warfare ;  but  a  certain  number  of  facts  of  physiological  interest 
in  connection  with  respiration  may  be  fitly  referred  to  here. 

The  first  serious  gas  attacks  were  made,  as  is  well  known,  with 


330  RESPIRATION 

chlorine,  discharged  into  the  air  in  a  good  breeze  as  "drift  gas" 
from  cylinders  of  liquefied  gas.  The  liquefied  gas  quickly  evapo- 
rated, thus  cooling  a  large  body  of  air  which  rolled  along  the 
ground,  producing  at  the  same  time  a  mist  if  the  air  was  nearly 
saturated,  and  passing  downwards  into  every  trench.  From  ac- 
counts given  by  officers  and  men  at  the  time,  I  estimated  that 
along  the  lines  attacked  there  was  usually  about  .01  per  cent  of 
chlorine  in  the  air;  but  of  course  the  percentage  would  vary.  At 
about  this  and  higher  concentrations,  chlorine  has  an  immediate 
and  severe  irritant  effect  on  the  air  passages,  and  a  less  severe 
action  on  the  eyes.  Bronchitis  follows  if  the  exposure  lasts  for 
more  than  a  very  short  time,  and  some  time  later  symptoms  of 
oedema  of  the  lungs  appear,  owing  to  the  action  of  the  gas  on  the 
alveolar  walls.  The  symptoms  are  then  similar  to  those  which 
follow  exposure  to  nitrous  fumes.  The  men  suffering  from  this 
condition  were  deeply  cyanosed,  with  superficial  veins  about  the 
neck  prominent,  greatly  increased  depth  and  rate  of  breathing, 
and  a  frequent,  but  usually  fairly  strong  pulse.  Intelligence  was 
clouded,  but  the  distress  seemed  very  great. 

On  testing  a  drop  of  blood  by  diluting  it  to  a  yellow  color, 
saturating  with  coal  gas  and  comparing  the  pink  tint  thus  pro- 
duced with  the  tint  of  normal  blood  similarly  diluted,  it  was  evi- 
dent that  there  was  no  decomposition  of  the  haemoglobin.  The 
cyanosis  was  therefore  due  to  imperfect  saturation  of  the  blood 
with  oxygen.  That  the  imperfect  saturation  was  due,  not  to  slow- 
ing of  the  circulation,  but  to  imperfect  saturation  in  the  lungs, 
was  shown  at  once  by  the  effect  of  giving  oxygen.  This  abolished 
the  cyanosis,  cleared  up  the  clouded  intelligence,  but  had  no  great 
effect  on  the  breathing.  On  post  mortem  examination  of  fatal 
cases  it  was  found  that  the  lungs  were  voluminous  and  greatly 
congested.  Large  quantities  of  albuminous  liquid  could  be 
squeezed  out  through  the  cut  bronchi,  and  there  was  much  em- 
physema. 

The  interpretation  of  the  more  dangerous  symptoms  seems 
fairly  clear.  The  cyanosis  was  due  to  the  fact  that  the  blood  in 
passing  through  the  lungs  was  imperfectly  oxygenated,  owing 
mainly  to  swelling  and  exudation,  which  hindered  the  diffusion 
of  oxygen  inwards  to  the  blood.  On  raising  the  alveolar  oxygen 
pressure  when  oxygen  was  given,  the  diffusion  became  much 
faster  and  the  blood  was  properly  oxygenated.  The  hyperpnoea 
remained,  however,  and  was  probably  attributable  to  the  fact 
that  though  much  air  was  entering  the  lungs,  a  great  deal  of  it 


RESPIRATION  331 

only  went  into  the  emphysematous  spaces  where  there  was  little 
or  no  circulation,  leaving  the  rest  of  the  lung  imperfectly  venti- 
lated, with  an  abnormal  excess  of  CO2  in  the  alveoli  which  were 
permeable  to  blood,  and  consequently  an  abnormal  excess  of 
breathing. 

Considering  the  depth  of  the  cyanosis  it  was  somewhat  re- 
markable that  consciousness  was  not  more  impaired;  but  the  ex- 
cess of  CO2  which  accompanied  the  cyanosis  would  of  course 
facilitate  the  dissociation  of  oxyhaemoglobin  in  the  tissue  capil- 
laries, and  thus  diminish  the  real  anoxaemia.  The  distention  of 
superficial  veins  was  an  indication  of  the  veno-pressor  effect  of 
excess  of  CO2  combined  with  failure  on  the  part  of  the  heart  to 
respond  normally  to  the  large  amount  of  blood  returning  to  it 
from  the  tissues.  This  failure  was  evidently  due  to  the  anoxaemic 
condition  of  the  blood  supplied  to  the  heart.  The  failure  was  pre- 
sumably most  marked  in  the  left  ventricle,  which  has  far  the  most 
work  to  do,  and  the  consequence  would  be  a  rise  of  blood  pressure, 
not  only  in  the  veins,  but  also  in  the  right  side  of  the  heart  and 
the  whole  pulmonary  circulation.  The  rise  in  pulmonary  blood 
pressure  would  of  course  tend  to  aggravate  greatly  the  oedema  of 
the  lungs,  and  would  thus  in  itself  be  a  very  serious  source  of 
danger.  The  ease  with  which  oedema  of  the  lungs  follows  on  in- 
creased venous  blood  pressure,  even  when  there  is  no  injury  to  the 
lungs,  has  been  shown  experimentally  by  Knowlton  and  Star- 
ling.26 

The  cause  of  the  greatly  increased  flow  of  blood  was  simply 
the  fact  that  the  arterial  blood  was  in  a  venous  condition,  with 
both  a  lowered  oxygen  pressure  and  raised  CO2  pressure.  The 
perfectly  normal  effect  of  this,  as  pointed  out  in  Chapter  X,  is  to 
cause  dilation  of  capillaries  and  increased  blood  flow  through  the 
tissues.  Owing,  however,  to  the  pressor  reaction  of  the  vasomotor 
center,  the  arterioles  and  probably  also  the  venules  in  most  parts 
of  the  body  except  the  central  nervous  system  were  contracted, 
and  in  this  way  the  blood  pressure  was  maintained,  so  that  the 
pulse  was  of  good  strength. 

It  was  first  observed  by  Macaulay  and  Irvine  of  Johannesburg 
that  in  the  treatment  of  cases  of  oedema  of  the  lungs  from 
poisoning  by  nitrous  fumes  in  mines,  great  benefit  is  often  ob- 
tained by  free  bleeding  to  the  extent  of  about  half  a  liter.  From 
the  foregoing  account  it  is  clear  that  bleeding  will  reduce  the 
venous  and  pulmonary  blood  pressure,  and  thus  also-  reduce  the 

M  Knowlton  and  Starling,  Journ.  of  Physiol.,  XLIV,  p.  206. 


332  RESPIRATION 

tendency  to  oedema  of  the  lungs.  The  indication  for  bleeding  is 
evidently  the  distention  of  superficial  veins.  Bleeding  was  fre- 
quently employed  in  the  treatment  of  the  chlorine  cases,  and  with 
great  success.  It  is  evident,  however,  that  if  there  is  no  venous 
distention,  bleeding  could  not  be  expected  to  do  anything  but 
harm. 

A  more  radical  treatment  is  the  continuous  administration  of 
air  enriched  with  oxygen.  Unfortunately  the  problem  of  con- 
tinuous administration  of  oxygen  had  never  been  attacked  before 
the  war,  and  no  suitable  apparatus  was  available  for  the  early 
chlorine  cases.  But  in  the  later  stages  of  the  war  many  cases  of 
lung  oedema  were  successfully  treated  continuously  with  oxygen 
by  means  of  a  nasal  tube  or  the  apparatus  described  in  Chapter 
VII. 

The  next  lung  irritant  gas  used  was  phosgene  (COC12).  This 
produces  dangerous  effects  in  considerably  lower  concentration 
than  chlorine,  and  its  action  is  distinguished  by  the  fact  that  it 
has  relatively  less  effect  on  the  air  passages  and  eyes  and  in  the 
end  more  on  the  alveolar  walls.  Thus  a  man  exposed  to  a  danger- 
ous concentration  of  phosgene  may  notice  but  little  irritant  effect 
at  the  time,  or  this  effect  may  pass  off  rapidly,  while  the  dangerous 
effects  on  the  alveoli  only  show  themselves  some  hours  later. 
Phosgene  was  at  first  used  as  drift  gas;  but  when  drift  gas  was 
abandoned  as  more  or  less  ineffective  against  the  protective 
measures  adopted,  and  also  unmanageable  owing  to  uncertain- 
ties of  wind,  etc.,  phosgene  was  largely  used  in  shells  or  bombs. 
Various  other  substances  with  similar  toxic  properties  were  also 
employed. 

A  change  in  the  type  of  the  symptoms  accompanying  lung 
oedema  was  now  noticed.  The  deep  plum-colored  cyanosis  and 
venous  distention  were  usually  absent,  and  bleeding  was  useless. 
The  cyanosis  was  still  very  marked,  but  was  of  a  pale  or  "gray" 
type.  The  breathing  was  also  shallower,  and  the  pulse  feeble  and 
rapid.  Many  slighter  cases  were  also  observed  in  which  no  defi- 
nite lung  symptoms  were  observed,  but  only  general  malaise  with 
cyanosis  and  fainting  on  any  muscular  exertion. 

In  all  these  cases  it  seems  evident  that  the  rate  of  diffusion  of 
oxygen  through  the  alveolar  walls  was  diminished,  but  without 
any  marked  interference  with  diffusion  of  CO2  outwards,  so  that 
owing  to  the  hyperpnoea  from  want  of  oxygen  there  would  be  a 
deficiency  of  CO2  in  the  arterial  blood.  This  is  very  intelligible 
in  view  of  the  fact  that  on  account  of  its  greater  solubility  COa 


RESPIRATION  333 

diffuses  outwards  from  the  blood  much  more  readily  than  oxygen 
diffuses  inwards  (see  Chapter  VIII).  The  deficiency  of  CO2  in 
the  arterial  blood  would  prevent  or  minimize  the  true  hyperpnoea, 
and  lessen  the  increase  of  circulation  through  the  tissue  capillaries 
and  the  pressor  excitation  of  the  vasomotor  center.  But  it  would 
increase  the  true  tissue  anoxaemia  with  a  given  degree  of  cyanosis. 
Anoxaemia  in  the  coronary  circulation  would  also  lead  to  the 
enfeebled  action  of  the  heart,  as  shown  by  the  very  weak  and 
feeble  pulse.  The  symptoms  generally  were  those  of  a  pure  anox- 
aemia with  urgent  danger  of  failure  of  the  respiratory  center  in 
the  manner  already  referred  to  in  Chapter  VI. 

In  these  cases  bleeding  was  of  course  useless.  On  the  other 
hand  injection  into  the  blood  of  saline  solution  or,  still  better, 
gum-saline,  seemed  likely  to  be  of  some  use  in  view  of  the  failing 
blood  pressure.  By  far  the  most  effective  treatment,  however,  was 
the  continuous  administration  of  air  enriched  with  oxygen,  par- 
ticularly if  this  was  begun  early  and  before  there  was  time  for  the 
dangerous  effects  which  continued  severe  anoxaemia  causes.  By 
this  means  the  oxygen  pressure  in  the  alveolar  air  was  sufficiently 
raised  to  permit  of  a  nearly  normal  aeration  of  the  arterial  blood ; 
and  the  administration  could  be  continued  till  the  lung  inflamma- 
tion subsided. 

The  chronic  after  effects  on  the  respiratory  center  of  irritant 
gases  have  already  been  referred  to  in  former  chapters. 


CHAPTER  XII 
Effects  of  High  Atmospheric  Pressures. 

THE  foundations  of  our  scientific  knowledge  of  the  physiological 
effects  of  high  and  low  atmospheric  pressures  were  laid  broad 
and  firm  b/  the  investigations  of  Paul  Bert,  collected  together  in 
his  book,  already  so  often  referred  to,  "La  Pression  Barome- 
trique,"  published  in  1878.  It  will  be  convenient  to  consider  first 
the  effects  of  high  atmospheric  pressures. 

Very  high  atmospheric  pressures  are  met  with  in  deep  diving 
and  in  engineering  work  under  water  or  in  water-logged  strata. 

Apart  from  laboratory  experiments  on  animals,  the  highest 
atmospheric  pressures  (up  to  ten  atmospheres)  have  been  met 
with  in  deep  diving.  To  understand  the  conditions  under  which 
a  diver  is  placed,  it  is  necessary  to  understand  the  design  of  the 
ordinary  diving  dress,  which  was  introduced  early  last  century  by 
Siebe,  the  founder  of  the  well-known  London  firm  of  manu- 
facturers of  diving  apparatus.  The  dress  consists  of  a  copper 
helmet  which  screws  on  to  a  metal  corselet,  the  latter  being 
clamped  water-tight  to  a  stout  waterproof  dress  covering  the 
whole  body  except  the  hands,  which  project  through  elastic  cuffs 
(Figures  75  and  76).  Air  is  supplied  to  the  diver  through  a  non- 
return valve  at  the  back  of  the  helmet  from  a  stout  flexible  pipe 
strengthened  with  steel  wire  and  connected  with  an  air  pump  at 
the  surface.  The  air  escapes  through  an  adjustable  spring  valve 
at  the  side  of  the  helmet  (Figure  77).  The  arrangement  is  thus 
such  that  the  pressure  of  air  in  the  helmet  is  at  least  equal  to,  and 
can,  by  varying  the  resistance  of  the  valve,  be  made  greater  than, 
the  water  pressure  at  the  outlet  valve.  For  every  34  feet  of  fresh 
water  (or  33  feet  or  10  meters  of  sea  water)  the  pressure  in- 
creases by  one  atmosphere,  or  nearly  15  pounds  per  square  inch. 
At  a  depth  of  33  feet  of  sea  water  the  diver  is  therefore  breathing 
air  at  an  excess  pressure  of  one  atmosphere,  or  a  total  pressure  of 
two  atmospheres.  It  is  absolutely  necessary  that  he  should  breathe 
compressed  air,  otherwise  his  breathing  would  be  stopped  in- 
stantly by  the  pressure  of  the  water  upon  the  abdomen ;  and  at  a 
greater  depth  blood  would  probably  pour  from  his  nose  and  mouth 
on  account  of  the  squeezing  to  which  all  parts  of  his  body,  except 
his  head  in  the  helmet,  would  be  subjected. 


Figure  75. 

Diving    dress,    front   view,    with    air   pipe    and    life    line, 
which  are  connected  with  the  helmet  behind. 


Figure  76. 

Diving  dress,  back  view,  showing  attachment  of  air  pipe 
and  life  line  with  telephonic  connection ;  new  pattern,  with 
legs  laced  up  to  prevent  diver  from  being  capsized  and 
accidentally  blown  up  to  surface,  or  hung  in  a  helpless 
position. 


RESPIRATION 


335 


In  order  to  enable  the  diver  to  sink  and  stand  firmly  on  the 
bottom,  the  dress  is  weighted  with  4O-pound  leaden  weights, 
back  and  forward,  as  shown,  with  16  pounds  of  lead  on  each 
boot — about  112  pounds  of  lead  in  all.  Besides  the  air  pipe,  the 
diver  is  connected  with  the  surface  by  a  so-called  life  line,  which 
usually  contains  a  telephone  wire.  He  goes  down  by  a  rope  at- 


Figure  77. 
Helmet  and  section  of  outlet  valve. 

tached  to  a  heavy  weight  which  has  been  lowered  to  the  bottom 
previously,  and  on  reaching  the  bottom  he  takes  with  him  a  line 
attached  to  this  weight,  so  that  he  can  always  find  the  rope  again. 
As  a  diver  enters  the  water,  the  superfluous  air  in  his  dress  is 
driven  out  through  the  outlet  valve  by  the  pressure  of  the  water 
round  his  legs  and  body.  The  water  seems  to  grip  him  all  round. 
If  the  valve  is  freely  open  he  feels  his  breathing  somewhat 


336  RESPIRATION 

labored  by  the  time  he  gets  first  under  water.  The  reason  of  this  is 
that  the  pressure  in  his  lungs  is  that  of  the  water  at  the  valve 
outlet,  whereas  the  pressure  on  his  chest  and  abdomen  is  greater 
by  something  like  a  foot  of  water.  He  is  thus  inspiring  against 
pressure,  and  if  he  has  to  breathe  deeply,  as  during  exertion,  the 
breathing  is  apt  to  become  fatigued  in  the  manner  described  in 
Chapter  III.  With  another  foot  of  adverse  pressure  the  fatigue  is 
very  rapid.  One  of  the  first  things  which  a  diver  has  to  learn  is 
to  avoid  the  adverse  pressure  by  regulating  the  spring  on  the 
outlet  valve,  so  that  the  breathing  is  always  easy.  The  spring 
regulates  at  the  same  time  the  amount  of  air  in  the  dress,  and 
therefore  the  buoyancy  of  the  diver.  A  practiced  diver  can  thus 
slip  easily,  and  without  exertion,  up  or  down  the  rope.  A  pres- 
sure gauge  attached  to  the  air  pipe  where  it  leaves  the  pump 
indicates  the  depth  of  the  diver  at  any  moment. 

The  breathing  is  of  course  easiest  when  the  dress  is  full  of  air 
down  to  the  level  of  the  diaphragm,  but  when  this  is  so  the  diver 
is  in  danger  of  being  "blown  up" ;  for  if  he  is  crawling  on  the 
ground,  it  may  easily  happen  that  the  air  gets  into  the  legs  of 
his  dress.  His  head  goes  down  so  that  the  excess  of  air  can- 
not escape  readily.  He  is  then  blown  helplessly  to  the  surface, 
while  his  arms  are  fixed  in  an  outstretched  position  (see  Figure 
78).  His  air  pipe  may  be  caught  by  a  rope  or  other  obstruction, 
so  that  he  is  hung  up  in  a  helpless  position  with  his  legs  upwards, 
the  excess  of  air  being  unable  to  escape  at  the  valve  since  it  is 
downwards.  In  very  deep  diving  there  is  considerable  risk  of 
being  blown  up ;  and  to  avoid  this  risk  the  arrangement  for  lacing 
up  the  legs,  shown  in  Figure  76,  was  introduced  (see  also  Fig- 
ure 79). 

In  the  Denayrouze  apparatus,  extensively  used  on  the  Conti- 
nent, the  air  is  pumped  into  a  steel  reservoir  on  the  diver's  back. 
By  means  of  a  reducing  valve  his  air  is  supplied  from  the  reser- 
voir according  to  his  requirements.  The  arrangement  is  a  beauti- 
ful piece  of  mechanism,  but  an  encumbrance  which  gives  rise  to 
various  inconveniences  and  dangers,  one  being  that  the  depth  of 
the  diver  cannot  be  read  off  at  the  surface,  and  another  that  he 
cannot  regulate  the  pressure  in  his  helmet. 

For  engineering  work  in  preparing  foundations,  etc.,  on  the 
sea  bottom,  a  diving  bell  is  sometimes  employed.  This  is  a  heavy 
metal  box,  open  below,  and  supplied  with  compressed  air  by  a 
pipe  (Figure  80).  It  is  lowered  to  the  bottom  with  the  workmen 
sitting  in  it,  and  they  can  work  dry  on  the  bottom.  The  diving 


Figure  78. 

Diver  in  ordinary  dress  blown  up.  His  head  is  down  and  his  arms 
outstreched. 


Figure  79. 

Diver  in  laced-up  dress  purposely  blown  up.  His  head 
is  up  and  his  arms  free. 


Figure  80. 

Diving  bell  in  use  at  National  Harbour  Works,  Dover.  Each  bell 
measures  17x10  feet  by  6  YZ  feet  high,  and  weighs  about  3  5  tons. 


Figure  81. 

Diagram  showing  use  of  caisson  in  making  the  foundations 
of  a  bridge.  (After  Foley.) 


RESPIRATION  337 

bell  in  its  crude  original  form  was  invented  by  Sturmius  in  the 
sixteenth  century,  and  further  developed  by  Halley  two  centuries 
later. 

The  caisson  introduced  about  1840  by  the  French  engineer 
Triger,  for  sinking  colliery  shafts  through  water-logged  strata 
near  the  surface,  is  a  further  development  of  the  diving  bell.  It 
is  now  largely  used  for  carrying  the  foundations  of  the  piers  of 
bridges,  etc.,  through  soft  ground  on  the  bottom  of  a  river  or  the 
sea.  The  caisson  (see  Figure  81)  is  the  bottom  section  of  the 
steel  pier,  and  resembles  a  diving  bell  except  for  the  fact  that  it 
communicates  with  surface  through  a  tube  occupying  the  center 
of  the  future  pier  and  kept  full  of  compressed  air.  This  tube 
serves  for  access  and  for  removal  of  excavated  material.  The  men 
excavate  the  soft  bottom  so  as  to  allow  the  caisson  to  sink  down 
to  a  secure  foundation,  and  the  sections  of  the  pier  are  added 
from  above  and  filled  with  concrete  as  the  caisson  sinks.  Access 
to  the  central  tube  is  through  an  air  lock  on  surface.  The  men 
enter  the  air  lock,  close  the  door,  and  then  let  the  air  pressure 
rise  till  they  can  open  the  door  into  the  central  tube ;  and  in  coming 
out  the  reverse  process  is  used. 

In  tunneling  operations  in  soft  strata  under  water,  the  ad- 
vancing tunnel  is  kept  full  of  compressed  air,  so  as  to  hinder  the 
penetration  of  water  into  the  advancing  end,  as  the  steel  rings 
forming  the  permanent  walls  of  the  tunnel  are  successively  put 
in.  The  men  thus  work  in  an  atmosphere  of  compressed  air,  to 
which  access  is  gained  through  one  or  more  air  locks.  The  tubes 
and  large  tunnels  under  the  Thames  or  deep  in  the  water-logged 
London  clay,  and  under  the  Hudson  and  East  Rivers  at  New 
York,  have  been,  or  are  being,  constructed  by  this  means.  In  the 
sinking  of  colliery  shafts  through  water-logged  strata  the  freez- 
ing or  cementation  processes  are  now  generally  used,  as,  except 
in  strata  fairly  near  the  surface,  the  water  pressures  are  too  high 
for  the  compressed-air  process. 

Various  physiological  disturbances  are  associated  with  ex- 
posure to  compressed  air,  and  these  must  now  be  considered  one  by 
one.  As  the  pressure  rises  when  a  man  goes  below  water,  in  a 
diver's  suit,  or  as  compressed  air  enters  an  air  lock  through  which 
he  is  passing  to  a  caisson  or  tunnel,  the  first  trouble  usually  noticed 
is  a  sense  of  pressure  and  pain  in  the  ears.  This  is  due  to  un- 
balanced pressure  on  the  membrana  tympani,  owing  to  the  fact 
that  the  Eustachian  duct  does  not  open  freely  so  as  to  equalize 
the  air  pressure  in  the  middle  ear  with  the  atmospheric  pressure 


338  RESPIRATION 

outside.  The  passage  is  specially  liable  to  be  blocked  if  any 
catarrh  of  the  air  passages  is  present ;  and  if  the  warning  pain  is 
disregarded  the  membrane  may  burst,  though  this  is  not  a  very 
serious  accident.  In  men  accustomed  to  compressed  air  the  Eus- 
tachian  tubes  open  easily,  so  that  no  inconvenience  is  felt,  and  a 
diver  goes  quite  easily  within  two  minutes  to  a  pressure  of  seven 
atmospheres  or  more,  while  one  who  is  not  accustomed  to  com- 
pressed air  may  have  a  long  struggle  with  his  Eustachian  tubes 
before  he  can  reach  an  extra  pressure  of  half  an  atmosphere.  It 
also  happens  occasionally  that  there  is  trouble  with  the  frontal 
sinuses.  The  same  difficulties  with  the  middle  ear  may,  of  course, 
be  met  with  by  airmen  during  rapid  descents,  or  even,  to  a  minor 
extent,  in  descending  a  deep  mine  shaft. 

A  man  who  has  reached  a  pressure  of  six  or  seven  atmospheres, 
and  is  breathing  pure  air,  is  perfectly  comfortable  if  he  has  es- 
caped ear  trouble.  His  voice  is,  however,  altered  by  the  com- 
pressed air,  and  this  is  so  marked  that  it  is  often  difficult  to  make 
out  through  the  telephone  what  he  is  saying.  At  first  sight  it 
might  seem  that  an  increased  mechanical  pressure  of  several 
atmospheres  would  in  itself  be  expected  to  have  an  appreciable 
effect  on  a  man  or  animal.  It  was  commonly  supposed,  for  ex- 
ample, that  the  increased  pressure  on  the  skin  must  at  first  tend  to 
drive  blood  into  the  internal  organs,  producing  congestion  of  the 
brain,  etc.,  with  a  converse  effect  on  diminishing  the  atmospheric 
pressure.  The  pressure  is,  however,  transmitted  instantly  through- 
out all  the  liquid  and  solid  tissues  of  the  body,  so  that  this  idea 
was  totally  fallacious,  and  indeed  ridiculous.  As  will  be  seen 
below,  many  divers  have  lost  their  lives  owing  to  well-meant  in- 
junctions to  descend  and  ascend  slowly.  As  regards  other  possible 
effects  of  a  few  atmospheres  of  mechanical  pressure,  it  should  be 
remembered  that  the  intrinsic  pressure  of  water  is  calculated  to 
be  over  10,000  atmospheres.  As  the  tissues  are  largely  composed 
of  water,  the  addition  to  this  of  a  few  atmospheres  of  mechanical 
pressure  in  the  liquid  or  semi-liquid  parts  of  the  body  cannot  be 
of  much  account. 

As  Paul  Bert  showed  experimentally,  the  serious  inconveni- 
ences and  dangers  to  which  workers  in  compressed  air  are  ex- 
posed are  due  (apart  from  easily  avoidable  effects  on  the  ears) 
not  to  the  mechanical  pressure,  but  to  the  increased  partial  pres- 
sures of  the  gases  in  the  air  breathed.  If  the  air  breathed  is  pure, 
the  only  gases  which  come  into  consideration  in  this  connection 
are  nitrogen  and  oxygen;  but  if  the  air  is  rendered  impure  by 


RESPIRATION  339 

respiration,  as  is  commonly  the  case  in  diving,  carbon  dioxide 
also  comes  into  consideration.  The  case  of  this  gas  may  be  con- 
sidered first,  though  Paul  Bert  did  not  himself  allude  to  it  in 
connection  with  work  in  compressed  air,  as  he  was  not  practically 
familiar  with  diving. 

Owing  to  the  difficulties  frequently  experienced  by  divers  in 
attempts  to  work  at  depths  over  about  12  fathoms  a  Committee, 
including  myself  as  the  physiological  member,  was  appointed  by 
the  British  Admiralty  to  investigate  the  whole  subject  of  the 
difficulties  and  dangers  associated  with  deep  diving.1  It  appeared 
that  men  who  attempted  to  make  any  serious  exertion  when  at 
depths  of  over  about  12  fathoms  often  became  unconscious  or 
greatly  exhausted.  The  symptoms  pointed  to  excess  of  CO2,  and, 
on  taking  samples  from  the  divers'  helmets  at  about  this  depth, 
we  frequently  found  2  or  3  per  cent  of  CO2.  This  occurred  in  spite 
of  an  apparently  abundant  supply  of  air  from  the  pumps,  which 
were  working  at  a  much  faster  rate  than  was  sufficient  to  keep  the 
diver  comfortable  at  a  lesser  depth.  As  explained  in  Chapter  II, 
the  physiological  effects  of  3  per  cent  of  CO2  at  1 1  fathoms,  or  a 
total  pressure  of  three  atmospheres,  is  equal  to  that  of  3  x  3  =  9 
per  cent  at  normal  atmospheric  pressure;  so  no  wonder  the  divers 
became  unconscious.  The  pumps  were  often  found  to  be  leaking 
badly  through  the  piston  rings,  as  many  of  them  were  old,  and 
no  tests  were  then  employed  to  detect  this  leakage.  Apart  from 
this  cause,  however,  the  air  supply  was  often  insufficient. 

It  is  evident  that  in  order  to  keep  down  the  pressure  of  CO2 
in  the  air  of  the  helmet  to  a  proper  limit,  the  amount  of  air  as 
measured  at  surface  by  the  strokes  of  the  pump  must  be  increased 
in  proportion  to  the  increase  in  the  total  atmospheric  pressure  in 
the  helmet.  The  diver  at  3  atmospheres  pressure,  requires,  there- 
fore, three  times  as  much  air,  and  so  on  in  proportion  to  the 
pressure.  When  this  was  attended  to,  and  the  piston  rings  kept 
tight,  no  discomfort  whatsoever  was  experienced  at  a  depth  of 
even  35  fathoms.  With  a  full  air  supply,  hard  exertion  is  actually 
easier  to  a  diver  at  some  depth  than  near  surface,  on  account  of 
the  higher  oxygen  pressure,  as  explained  in  Chapter  IX. 

By  far  the  most  serious  danger  to  divers  and  other  workers  in 
compressed  air  is  of  a  quite  different  character.  From  the  earliest 
days  of  diving  and  work  in  compressed  air  it  had  been  observed 
that  soon  after  returning  to  atmospheric  pressure  the  men  fre- 

1  Re-port  of  the  Admiralty  Committee  on  Deep  Water  Diving,  Parl.  Paper,  C.  N., 
1549,  1907. 


340  RESPIRATION 

quently  became  ill,  and  sometimes  died  or  became  paralyzed. 
The  risk  of  these  attacks  increased  with  the  pressure  and  the 
duration  of  exposure  to  it,  but  they  never  occurred  except  on 
return  to  atmospheric  pressure.  Divers  are  exposed  to  the  highest 
pressures,  and  in  divers  the  attacks  were  of  the  most  dangerous 
character.  In  the  worst  cases  the  diver  began  to  feel  faint  a  few 
minutes  after  return  to  surface ;  soon  he  became  unconscious 
and  his  pulse  disappeared;  and  in  a  few  minutes  he  was  dead. 
In  other  cases  his  legs  became  paralyzed,  and  cases  of  "diver's 
paralysis"  used  to  be  not  uncommon  in  British  hospitals.  In  the 
slighter  cases,  very  common  among  workers  in  caissons  and  tun- 
nels under  construction,  there  is  severe  pain,  known  to  the  work- 
men as  "bends,"  in  one  or  other  of  the  limbs,  or  in  the  body. 
Another  of  the  common  slight  symptoms  is  itching  of  the  skin. 
Various  other  nervous  symptoms  are  also  met  with,  the  whole 
complex  being  designated  as  "caisson  disease" —  a  somewhat  mis- 
leading name. 

Paul  Bert  investigated  on  animals  the  nature  of  compressed 
air  illness  or  "caisson  disease,"  and  found  that  it  is  due  to  libera- 
tion in  the  blood  and  tissues  of  bubbles  of  gas  consisting  almost 
entirely  of  nitrogen.  In  the  rapidly  fatal  cases  the  heart  becomes 
filled  with  a  mass  of  bubbles  which  stop  the  whole  circulation. 
In  the  cases  of  paralysis  bubbles  have  obstructed  the  circulation 
and  so  caused  necrosis  of  parts  of  the  spinal  cord ;  and  it  is  evi- 
dent that  the  bubbles  may  produce  the  most  varied  symptoms 
according  to  the  positions  in  which  they  are  formed. 

The  cause  of  the  bubble  formation  was  evident.  At  the  high 
pressure  the  blood  in  the  lungs  is  exposed  to  greatly  increased 
partial  pressures  of  nitrogen  and  oxygen,  although,  as  shown  in 
Chapter  II,  there  is  no  increased  pressure  of  CO2.  As,  in  ac- 
cordance with  Henry's  law,  liquids  take  up  in  simple  solution  a 
mass  of  any  gas  proportional  to  its  partial  pressure,  the  blood  in 
the  lungs  takes  up  in  the  compressed  air  an  extra  amount  of  nitro- 
gen and  oxygen  proportional  to  the  increased  pressure.  The  extra 
oxygen  disappears  at  once  when  the  blood  reaches  the  tissues,  but 
the  extra  nitrogen  does  not  disappear,  and  gradually  saturates 
the  whole  of  the  tissues  till  they  are  charged  with  nitrogen  at  the 
partial  pressure  existing  in  the  air  breathed.  When  the  external 
atmosphere  is  reduced  to  normal,  the  internal  partial  pressure  of 
nitrogen  is  of  course  far  above  the  atmospheric  pressure.  The 
blood  and  tissues  are  therefore  supersaturated  with  nitrogen  and 
bubbles  begin  to  form.  These  bubbles  consist  primarily  of  nitro- 


Figure  82. 

Portion  of  goat's  mesentery  showing  bubbles  in  blood  vessels  caused  by 
rapid  decompression  in  1^2  minutes  from  100  Ibs.  pressure,  after  ij^  hours 
exposure  at  this  pressure. 


RESPIRATION  341 

gen,  but  of  course  take  up  a  little  oxygen  and  CO2  from  the  sur- 
rounding blood  and  tissue  liquids.  If  they  are  formed  in  the  blood 
they  tend  to  block  the  circulation  on  account  of  the  great  resist- 
ance which  they  cause.  Figure  82  is  from  a  photograph  of  blood 
vessels  in  the  mesentery  of  a  goat  killed  by  rapid  decompression, 
and  shows  abundant  bubbles  in  the  veins. 

The  bubbles  are  formed,  not  merely  in  the  blood,  but  also  in 
the  tissues  outside  it.  We  found  that  fat  in  particular  is  apt  to  be 
very  full  of  bubbles  and  thus  become  spongy.  It  had  been  found 
by  Vernon  in  connection  with  another  investigation  that  gases 
are  much  more  soluble  in  oils  than  in  water.  In  connection  with 
our  investigations  he  determined  the  solubility  of  nitrogen  in 
body  fats  at  blood  temperature,  and  found  that  it  is  about  six 
times  as  great  as  in  water.2  The  tendency  of  fatty  substances  to 
act  as  a  special  reservoir  of  dissolved  nitrogen  is  thus  intelligible ; 
and  Boycott  and  Damant3  afterwards  showed  that  fat  animals, 
other  conditions  being  the  same,  are  considerably  more  liable  to 
symptoms  of  caisson  disease  than  spare  animals.  Not  only  ordi- 
nary fat,  but  the  myelin  sheaths  of  nerve  fibers,  will  form  reser- 
voirs of  dissolved  nitrogen;  and  for  this  reason  bubbles  will  tend 
to  be  liberated  in  the  white  matter  of  the  brain  and  spinal  cord, 
and  inside  the  sheaths  of  large  nerves.  The  "bends"  and  certain 
other  associated  symptoms  from  which  workers  in  compressed 
air  so  frequently  suffer  are  probably  due  to  liberation  of  bubbles 
from  the  gas  dissolved  in  the  myelin  sheaths.  It  is  difficult  to  un- 
derstand otherwise  the  severe  pain  of  "bends."  Figure  83  shows 
the  positions  of  a  large  number  of  bubbles  found  in  the  white 
matter  at  different  parts  of  the  spinal  cord. 

The  increased  amount  of  nitrogen  dissolved  in  the  blood  at 
high  atmospheric  pressures  was  demonstrated  by  Paul  Bert  by 
blood-gas  analyses ;  and  Hill  and  Greenwood4  not  only  confirmed 
this,  but  showed  that  there  is  the  same  excess  in  the  urine.  Hill 
and  Macleod  also  observed  directly  the  sudden  appearance  of 
gas  bubbles  in  the  capillaries  of  the  frog's  web  when  the  animal 
was  decompressed  from  a  high  atmospheric  pressure.5 

As  a  preventive  of  the  occurrence  of  caisson  disease  Paul  Bert 
recommended  slow  and  gradual  decompression;  but  his  experi- 
ments in  this  direction  were  not  very  successful,  as  he  had  not 

2  Vernon,  Proc.  Roy.  Soc.,  LXXIX,  B,  p.  366,   1907. 

3  Boycott  and  Damant,  Journ.  of  Hygiene,  VIII,  p.  445,  1908. 
*Hill  and  Greenwood,  Proc.  Roy.  Soc.,  LXXIX,  B,  p.  21,  1907. 
'Hill  and  Macleod,  Journ.  of  Hygiene,  III,  p.  436,  1903. 


342 


RESPIRATION 


2nd  cervical. 


3rd  dorsal. 


Figure  83. 

Shows  the  distribution  of  extravascular  bubbles  in  five  regions  of  the  spinal 
cord  of  goat  3  (series  IV).  The  animal  died  of  oxygen  poisoning  during  de- 
compression after  3  hours'  exposure  at  81  Ibs.  in  an  atmosphere  containing 
36  per  cent  oxygen.  The  bubbles  are  practically  confined  to  the  white  matter 
and  are  there  especially  concentrated  in  the  boundary  zone  where  the  circula- 
tion is  least  good.  Each  diagram  is  a  composite  drawing  showing  all  the  bubbles 
in  0.4  mm.  length  of  cord.  (After  Boycott,  Damant,  and  Haldane.) 


RESPIRATION  343 

completely  realized  the  conditions.  Slow  and  uniform  decompres- 
sion was,  and  still  is,  also  enjoined  by  various  government  regu- 
lations, etc.,  in  different  countries,  but  with  only  very  moderate 
success;  and  deaths  or  paralyses  from  caisson  disease  remained 
common  if  the  extra  pressure  used  was  above  about  1.5  atmos- 
pheres. Workers  in  compressed  air  had  soon  discovered  that  the 
pain  of  "bends"  can  be  relieved  at  once  by  returning  into  the  com- 
pressed air;  and  this  became  quite  intelligible  from  Paul  Bert's 
experiment.  He  made  some  experiments  on  the  curative  effects 
of  recompression,  but  here  again  he  was  not  very  successful,  as 
he  applied  the  remedy  only  in  extreme  cases.  Medical  recompres- 
sion chambers  for  the  treatment  of  compressed  air  illness  were 
first  introduced  by  Sir  Ernest  Moir  in  connection  with  the  con- 
struction of  the  first  East  River  tunnel  at  New  York,  and  the 
Blackwall  Tunnel  under  the  Thames,  about  1890.  They  proved 
strikingly  successful  when  applied  to  the  cases  which  occurred 
with  the  comparatively  slow  decompression  in  the  air  lock.  Pa- 
ralyses and  "bends"  were  relieved  at  once,  even  when  they  had 
occurred  a  considerable  time  after  leaving  the  tunnel.  The  pro- 
vision of  medical  recompression  chambers  has  now  become  a 
necessary  adjunct  of  all  considerable  engineering  undertakings 
at  pressures  of  over  about  1.5  atmospheres,  and  in  extensive  deep 
diving  operations.  Figures  84  and  85  show  one  of  the  recompres- 
sion chambers  used  in  the  British  Navy.  The  trouble,  however, 
about  the  use  of  recompression  chambers  is  that  it  is  often  very 
difficult  to  get  the  patient  out  without  the  symptoms  recurring. 
The  decompression  may  require  many  hours,  or  even  days  in  bad 
cases. 

Paul  Bert  also  tried  another  method  of  treatment — that  of 
administering  pure  oxygen  to  his  animals.  This  must  hasten  the 
diffusion  outwards  of  nitrogen,  while  the  oxygen  itself  is  ab- 
sorbed by  the  tissues.  At  first  sight  it  might  seem  as  if  this  plan 
ought  to  be  very  successful,  either  in  treatment  or  in  the  pre- 
vention of  bubble  formation  during  decompression.  The  results, 
however,  were  disappointing  and  from  causes  which  will  be  made 
evident  below.  There  seems,  however,  to  be  some  scope  for  oxy- 
gen administration  where  there  is  great  difficulty  in  getting  a 
patient  out  of  a  medical  air  lock,  and  where  there  is  no  fear  of 
oxygen  poisoning — a  condition  which  will  be  discussed  presently. 

When  the  Admiralty  Committee  had  dealt  with  the  troubles 
traced  to  CO2,  it  was  faced  by  the  dangers  of  caisson  disease, 
which  of  course  became  much  more  important  after  it  had  been 


344  RESPIRATION 

rendered  possible  for  divers  to  work  at  great  depths  without  in- 
convenience. The  existing  precautions  against  "caisson  disease" 
were  evidently  quite  insufficient.  The  divers  were  officially  en- 
joined to  descend  and  come  up  at  a  slow  and  even  rate  of  about 
5  feet  per  minute,  but  many  serious  or  fatal  cases  were  occurring 
in  spite  of  this.  The  problem  was  to  find  a  safe  and  reasonably 
short  method.  Very  slow  methods  are  impractible  on  account  of 
changes  of  tides  and  weather.  The  whole  physiological  side  of 
compressed-air  illness  had  therefore  to  be  reconsidered. 

The  formation  of  bubbles  depends,  evidently,  on  the  existence 
of  a  state  of  supersaturation  of  the  body  fluids  with  nitrogen. 
Nevertheless  there  was  abundant  evidence  that  when  the  excess 
of  atmospheric  pressure  does  not  exceed  about  i%  atmospheres 
there  is  complete  immunity  from  symptoms  due  to  bubbles,  how- 
ever long  the  exposure  to  the  compressed  air  may  have  been,  and 
however  rapid  the  decompression.  Thus  bubbles  of  nitrogen  are 
not  liberated  within  the  body  unless  the  supersaturation  corre- 
sponds to  more  than  a  decompression  from  a  total  pressure  of 
2/4  atmospheres.  Now  the  volume  of  nitrogen  which  would 
tend  to  be  liberated  is  the  same  when  the  total  pressure  is  halved, 
whether  that  pressure  be  high  or  low.  Hence  it  seemed  to  me 
probable  that  it  would  be  just  as  safe  to  diminish  the  pressure 
rapidly  from  4  atmospheres  to  2,  or  6  atmospheres  to  3,  as  from 
2  atmospheres  to  i.  If  this  were  the  case,  a  system  of  stage 
decompression  would  be  possible,  and  would  enable  the  diver  to 
get  rid  of  the  excess  of  nitrogen  through  his  lungs  far  more 
rapidly  than  if  he  came  up  at  an  even  rate.  The  duration  of  ex- 
posure to  a  high  pressure  could  also  be  shortened  very  consid- 
erably, without  shortening  the  period  available  for  work  on  the 
bottom. 

The  whole  matter  was  put  to  the  test  in  a  long  series  of  experi- 
ments carried  out  on  goats  by  Professor  Boycott,  Commander 
Damant,  and  myself6  at  the  Lister  Institute,  London,  in  a  large 
steel  chamber  which  was  given  for  the  purpose  by  the  late  Dr. 
Ludwig  Mond  (see  Figures  86  and  87).  We  found  that  after 
very  long  exposure  of  a  number  of  the  animals  at  a  total  pressure 
of  6  atmospheres  sudden  decompression  to  2.6  atmospheres  pro- 
duced not  the  slightest  ill  effect.  This  decompression  is  in  the 
proportion  of  2.3  to  I,  and  the  drop  of  pressure  was  3.4  atmos- 
pheres. In  a  corresponding  series  where  the  drop  of  pressure  was 

a  Boycott,  Damant,  and  Haldane,  Journ.  of  Hygiene,  VIII,  p.  242,  1908.  The 
Report  of  the  Admiralty  Committee  contains  a  short  abstract  of  the  work. 


Figure  84. 

Outside  of  naval  recompression  chamber,  showing  man- 
hole for  access,  and  air  lock  for  food. 


Figure  85. 
Inside  of  recompression  chamber,  showing  bed  for  patient. 


O  +3 
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Us 


RESPIRATION  345 

the  same,  but  from  4.4  to  I  atmosphere,  or  in  the  proportion  of 
4.4  to  i,  only  20  per  cent  of  the  animals  escaped  symptoms,  while 
20  per  cent  died,  30  per  cent  had  severe  symptoms,  and  30  per 
cent  had  "bends,"  quite  easily  recognized  in  the  animals  by  their 
behavior  and  the  manner  in  which  they  held  the  affected  limb 
(Figure  88).  It  seemed  evident,  therefore,  that  it  is  quite  safe  to 
halve  the  absolute  pressure  rapidly.  Before  venturing  on  such 
extensive  rapid  decompressions  of  divers  under  water  we  re- 
peated the  goat  experiments  on  men  in  the  steel  chamber,  Com- 
mander Damant  and  Lieutenant  Catto  being  the  subjects.  There 
were  no  ill  effects  in  a  number  of  experiments,  nor  in  subsequent 
trials  by  them  under  water  at  sea;  and  rapid  decompression  to 
half  the  absolute  pressure  is  now  the  routine  practice  of  divers, 
and  is  not  known  to  have  ever  resulted  in  harm. 

We  were  still,  however,  only  at  the  beginning  of  the  inquiry. 
It  was  evident  that  the  whole  danger  lay  in  the  last  stages  of  the 
decompression.  "On  ne  paie  qu'en  sortant,"  as  was  remarked  by 
Pol  and  Watelle,  who  were  the  first  to  give  a  medical  account  of 
the  symptoms  of  caisson  disease.7  The  problem  was  to  get  divers 
completely  clear  of  the  compressed  air  without  paying.  This 
problem  had  resolved  itself  into  that  of  avoiding  the  critical 
supersaturation  with  nitrogen  in  any  part  of  the  body  at  or  before 
the  last  stage  of  decompression. 

Let  us  consider  the  process  of  saturation  and  desaturation  more 
closely.  The  blood  passing  through  the  lungs  of  a  man  breathing 
compressed  air  will,  in  accordance  with  what  has  been  explained 
in  Chapter  IX  as  to  the  permeability  of  the  lung  epithelium  to 
gas,  become  instantly  saturated  to  the  full  extent  with  nitrogen 
at  the  existing  partial  pressure  in  the  air.  When  this  blood 
reaches  the  systemic  capillaries,  most  of  the  excess  of  nitrogen 
will  diffuse  out  and  the  blood  will  return  for  a  fresh  charge,  this 
process  being  repeated  until  at  length  the  tissues  are  fully  charged 
with  nitrogen  at  the  same  partial  pressure  as  in  the  air.  But  the 
blood  supply  to  different  parts  of  the  body  varies  greatly,  as  we 
have  seen.  The  capacity  of  different  parts  of  the  body  for  dis- 
solving nitrogen  varies  also.  Thus  the  white  matter  of  the  central 
nervous  system  has  but  a  small  blood  supply  and  at  the  same  time  a 
high  capacity  for  storing  nitrogen ;  and  the  same  remark  applies  to 
fat.  The  gray  matter,  on  the  other  hand,  has  an  enormous  blood 
supply  and  no  extra  capacity  for  storing  nitrogen.  Other  tissues, 
such  as  muscles,  may  or  may  not  have  a  great  blood  supply,  ac- 

TPol  et  Watelle,  Ann.  d,' hygiene  -pubUqiie,  (2),  p.  241,  1854. 


346  RESPIRATION 

cording  to  the  amount  of  work  a  man  is  doing.  We  can  easily 
see,  therefore,  that  the  time  taken  for  different  parts  of  the  body 
to  become  saturated  with  nitrogen  will  vary  greatly. 

Taking  into  consideration  the  amount  of  fatty  material  in  the 
body,  we  estimated  that  the  whole  body  of  a  man  weighing  70 
kilos  will  take  up  about  I  liter  of  nitrogen  for  each  atmosphere 
of  excess  pressure — about  70  per  cent  more  nitrogen  than  an 
equal  weight  of  blood  would  take  up.  Now  the  weight  of  blood  in  a 
man  is  about  6.5  per  cent  of  the  body  weight;  hence  the  amount 
of  nitrogen  held  in  solution  in  the  body,  when  it  is  completely 

saturated  with  nitrogen,  will  be  about  — —    or  26  times  as  great 

as  the  amount  held  in  the  blood  alone.  If,  therefore,  the  composi- 
tion of  the  body  were  the  same  at  all  parts,  and  the  blood  dis- 
tributed itself  evenly  to  all  parts,  the  body  would  have  received  at 
one  complete  round  of  the  blood  after  sudden  exposure  to  a  high 
pressure  of  air  one  twenty-sixth  of  the  excess  of  nitrogen  cor- 
responding to  complete  saturation.  The  second  round  would 
add  one  twenty-sixth  of  the  remaining  deficit  in  circulation,  i.e., 
1/26  x  25/26  of  the  total  excess.  The  third  round  would  add 
1/26  x  (25/26  x  25/26),  and  so  on.  On  following  out  this  calcu- 
lation, it  will  be  seen  that  the  body  would  be  half  saturated  in 
less  than  20  rounds  of  the  circulation,  or  about  ten  minutes,  and 
that  saturation  would  be  practically  complete  in  an  hour.  The 
progress  of  the  saturation  would  follow  the  logarithmic  curve 
shown  in  Figure  89.  Actually  the  rate  of  saturation  will  vary 
widely  in  different  parts  of  the  body ;  but  for  any  particular  part 
the  rate  of  saturation  will  follow  a  curve  of  this  form,  assuming 
that  the  circulation  rate  is  constant. 

There  is  abundant  evidence,  both  from  human  experience  and 
from  experiments  on  animals,  that  liability  to  compressed-air 
illness  increases  with  duration  of  exposure.  We  found  that  in 
goats  the  liability  increased  up  to  about  3  hours'  exposure,  but 
did  not  increase  further  even  with  far  longer  exposure.  In  man, 
on  the  other  hand,  limitation  of  exposure  to  3  hours  has  been 
found  to  diminish  the  liability  distinctly,  and  we  calculated  from 
the  goat  experiments,  taking  into  account  the  greater  rate  of 
circulation  in  the  goat  on  account  of  its  much  smaller  weight  (see 
Chapter  X),  that  in  man  the  liability  would  increase  up  to  about 
5  hours'  exposure.  We  had  therefore  to  allow  for  parts  of  the 
body  which  would  only  become  half  saturated  in  about  1^4  hours, 
but  for  nothing  slower  than  this. 


Figure  88. 
"Bends"  of  foreleg  in  a  goat. 


RESPIRATION 


347 


The  longer  any  part  of  the  body  takes  to  saturate,  the  longer 
will  it  also  take  to  desaturate  to  the  point  at  which  it  is  safe  to 
reduce  the  pressure  to  normal.  But  if  we  know  the  pressure  and 
duration  of  exposure,  we  can  now  calculate  a  safe  rate  of  further 
decompression  after  the  initial  reduction  of  total  pressure  to  half 


IUU 

.  —  — 

• 

^ 

^^ 

/ 

' 

60 
50 

/ 

/ 

/ 

30 

10 

n 

1 

1 

/ 

Multiples  of  the  time  required  to  produce  half -saturation. 

Figure  89. 

Curve  showing  the  progress  of  saturation  of  any  part  of  the  body 
with  nitrogen  after  any  given  rise  of  pressure.  The  percentage 
saturation  can  be  read  off  on  the  curve,  provided  the  duration  of 
exposure  to  the  pressure,  and  the  time  required  to  produce  half  satu- 
ration of  the  part  in  question,  are  both  known.  Thus  a  part  which 
half  saturates  in  one  hour  would,  as  shown  on  the  curve,  be  30  per 
cent  saturated  in  half  an  hour,  or  94  per  cent  saturated  in  4  hours. 

has  been  carried  out :  for  we  can  calculate  the  rate  at  which  nitro- 
gen is  being  carried  away  from  parts  which  saturate  and  de- 
saturate  quickly,  or  from  those  which  do  so  slowly.  We  can  thus 
regulate  the  rate  of  decompression  so  that  no  part  of  the  body 
is  at  any  time  supersaturated  to  such  an  extent  as  to  cause  risk  of 
bubble  formation.  In  this  way  tables  were  calculated  for  regu- 
lating the  rate  of  decompression  of  divers  and  other  workers  in 
compressed  air.  For  the  sake  of  convenience  the  decompression 


348 


RESPIRATION 


rate  was  calculated  in  stages,  each  of  which  represents  a  reduc- 
tion in  depth  of  10  feet,  so  that  a  diver  is  stopped  by  signal  at  every 
ten  feet  of  ascent. 

Figure  90  represents  what  is  happening  during  a  dive  to  28 
fathoms,  with  the  stay  on  the  bottom  limited  to  14  minutes,  and 


Figure  90. 

Diving  to  168  feet  by  new  method:  Diver  14  minutes  on  the  bottom  and  46 
minutes  under  water.  The  curves  from  above  downward  represent,  respectively, 
the  variations  in  saturation  of  parts  of  the  body  which  half  saturate  in  5,  10,  20, 
40,  and  75  minutes;  the  thick  line  representing  the  air  pressure. 


the  new  method  carried  out  of  rapid  descent  and  ascent  by  stages. 
It  will  be  seen  that  when  the  diver  reaches  surface,  the  maximum 
condition  of  supersatu ration  with  nitrogen  in  any  part  of  the  body 
corresponds  to  only  17/4  pounds  per  square  inch  (or  1.17  atmos- 
pheres) of  air  pressure.  This  leaves  a  margin  of  safety.  Figure  91 
shows  what  happened  by  the  old  method,  with  the  same  time  on 


RESPIRATION 


349 


the  bottom.  It  will  be  seen  ( I )  that  the  dive  took  twice  as  long  a 
time,  and  (2)  that  when  he  reached  surface  the  maximum  super- 
saturation  was  36  Ibs.  (2.4  atmospheres),  so  that  he  would  run  a 


15 


10        IS       20        25       30       JS       40       45       SO       SS       6O       6S 

Time  in  minutes. 


75       8O 


Figure  91. 

Diving  to  168  feet  by  old  method:  Diver  14  minutes  on  the  bottom  and  84 
minutes  under  water.  The  curves  from  above  downward  represent,  respectively, 
the  variations  in  saturation  of  parts  of  the  body  which  half  saturate  in  5,  10,  20, 
40,  and  75  minutes;  the  thick  line  representing  the  air  pressure. 

most  dangerous  risk.  It  is  evident  from  the  figure  that  the  slow 
descent  and  most  of  the  slow  ascent  were  simply  adding  to  the 


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Figure  92. 

Theoretical  ascents  of  a  diver  after  a  prolonged  stay  at  213  feet  of  sea 
water.  Stage  decompression  in  309  minutes  compared  with  uniform  decom- 
pressions in  309  minutes  and  in  10  hours.  Continuous  lines  =  stage  decompres- 
sion :  interrupted  lines  =  uniform  decompression.  Thick  lines  =  air  pressure : 
thin  lines  =  saturation  with  atmospheric  nitrogen  in  parts  of  the  body  which 
half  saturate  in  75  minutes. 


350  RESPIRATION 

danger.  These  figures  show  also  in  a  clear  way,  the  advantages  of 
cutting  down  the  duration  of  stay  on  the  bottom.  It  appears  from 
Figure  90  that  with  the  short  stay  on  the  bottom  the  more  slowly 
saturating  parts  of  the  body  have  not  time  to  reach  a  dangerous 
degree  of  saturation,  though  they  might  do  so  if  similar  dives 
were  repeated  after  short  intervals  on  one  day. 

With  a  long  exposure  to  a  high  air  pressure  the  time  required 
for  safe  decompression,  even  by  the  stage  method,  becomes  much 
too  long  for  ordinary  diving  work.  Figure  92  shows,  for  instance, 
that  it  would  take  nearly  five  hours  by  the  stage  method,  and  ten 
hours  with  uniform  decompression,  for  completely  safe  decom- 
pression after  a  stay  of  some  hours  under  a  pressure  of  35^2 
fathoms  of  water,  or  an  excess  pressure  of  6J^  atmospheres. 
In  the  ordinary  diving  table,  therefore,  the  stay  on  the  bottom  is 
so  limited  that  the  diver  can  be  decompressed  safely  in  half  an 
hour.  Nevertheless,  it  may  happen  that  it  is  justifiable  to  stay 
longer,  or  that  a  diver's  air  pipe  is  fouled  by  something  on  a  wreck 
and  even  that  he  cannot  be  liberated  till  the  tide  slackens  or  turns. 
To  meet  such  cases  a  supplementary  table  was  drawn  up.  These 
two  tables  are  reproduced  below. 

Since  the  introduction  into  the  British  Navy  twelve  years  ago 
of  the  method  of  decompression  embodied  in  the  tables,  with  the 
corresponding  regulations  as  to  air  supply  and  testing  of  the 
pumps,  deep  diving  has  been  conducted  with  comfort  and  safety 
to  the  divers,  so  that  compressed-air  illness  has  now  practically 
disappeared  except  in  isolated  cases  where  from  one  cause  or 
another  the  regulations  have  not  been  carried  out.  When  a  medi- 
cal compressed-air  chamber  is  available,  it  is  justifiable  to  cut 
down  the  time  for  the  last  wearisome  stages  of  the  decompression, 
and  so  extend  the  time  on  the  bottom.  This  has  been  cautiously 
tried  under  Commander  Damant's  supervision,  but  the  result  was 
that  the  divers  began  to  suffer  from  "bends."  These  could  easily 
be  relieved  in  the  chamber,  but  much  loss  of  time  and  incon- 
venience resulted,  and  the  "bends"  were  apt  to  recur.  It  seemed 
better  to  keep  the  chamber  as  a  precaution  against  emergencies  or 
unforeseen  accidents.  I  calculated  the  tables  with  great  care  on 
the  theoretical  lines  borne  out  by  the  experiments  and  in  the 
light  of  all  the  available  evidence  from  human  experience ;  and  it 
appears  that  the  times  cannot  be  cut  down  without  risk  of  trouble, 
unless  the  divers  are  placed  in  the  chamber  as  a  matter  of  routine 
after  each  dive. 

If  a  diver  develops  serious  symptoms  of  compressed-air  illness, 


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RESPIRATION  351 

and  no  compressed-air  chamber  is  available,  the  best  plan  is  to 
screw  on  his  helmet  and  drop  him  down  under  water  till  his 
symptoms  disappear.  An  unconscious  man  (who  had  developed 
bad  symptoms  as  a  result  of  disregarding  orders  to  stop  at  the 
proper  stages)  soon  answered  the  telephone  when  he  was  dropped 
down  in  this  way.  The  trouble,  however,  is  to  get  the  man  up 
again  safely.  A  very  cautious  ascent  is  needed.  When  once  bubbles 
of  any  considerable  size  have  formed  it  takes  a  considerable  time 
to  get  them  redissolved. 

The  reason  why  a  bubble  in  the  blood  or  elsewhere  in  the  body 
tends  to  disappear,  is  that  the  partial  pressure  of  nitrogen  in  the 
bubble  is  greater  than  in  the  blood.  The  blood  is  saturated  in  the 
lungs  with  nitrogen  at  a  pressure  of  about  75  per  cent  of  the 
existing  atmospheric  pressure.  In  the  venous  blood,  and  there- 
fore in  the  tissues,  the  pressure  of  oxygen,  as  shown  in  Chapter  X, 
is  only  about  6  per  cent  and  of  CO2  about  6.5  per  cent  of  an 
atmosphere.  There  is  also  a  pressure  of  about  6  per  cent  of  aqueous 
vapor.  As  the  bubble  is  at  atmospheric  pressure  and  the  total  gas 
pressure  in  the  surrounding  tissues  is  only  about  75  -}-  18.5  = 
93.5  per  cent  of  an  atmosphere,  its  nitrogen  pressure  is  above  that 
of  the  tissues  by  6.5  per  cent.  It  must  therefore  gradually  go  into 
solution,  and  at  high  atmospheric  pressures  it  will  do  so  all  the 
sooner  since  the  pressures  of  oxygen  and  CO2  do  not  increase  pro- 
portionally to  the  atmospheric  pressure.  If  the  bubbles  are  only 
very  small  they  will  probably  dissolve  very  rapidly  on  recompres- 
sion;  but  if  they  are  large,  and  particularly  if  they  have  been 
formed  at  places  where  there  is  but  little  circulation,  they  will  take 
a  long  time  to  disappear.  Great  patience  may  therefore  be  needed 
in  treatment  by  recompression. 

In  the  experiments  made  at  sea  under  the  direction  of  the 
Admiralty  Committee,  the  greatest  depth  at  which  trials  were 
made  was  35  fathoms.  At  this  depth  Commander  Damant  and 
Lieutenant  Catto  were  perfectly  comfortable,  and  in  all  the 
numerous  experimental  dives  which  they  made  up  to  this  depth 
with  stage  decompression,  no  symptoms  whatever  of  compressed- 
air  illness  were  observed.  This  depth  was,  however,  greatly  ex- 
ceeded in  the  course  of  operations  for  the  recovery  of  a  United 
States  submarine  at  Honolulu  in  1915.  A  diving  crew  had  been 
trained  in  the  new  methods  at  New  York,  and  proceeded  to  Hono- 
lulu to  assist  in  getting  hawsers  in  position  round  the  submarine, 
which  was  lying  at  a  depth  of  50  fathoms  (corresponding  to  an 
excess  pressure  of  over  9  atmospheres  or  135  pounds  per  square 


352  RESPIRATION 

inch).  The  operations  were  successful,  and  these  remarkable 
dives  are  described  in  a  paper  by  Assistant  Surgeon  French, 
U.  S.  N.,  who  was  one  of  the  medical  officers  in  immediate 
charge.8 

Eleven  dives  were  made  to  depths  of  from  306  to  270  feet,  the 
time  on  the  bottom  being  usually  about  20  minutes.  The  stage 
decompression,  which  was  shortened  as  a  recompression  chamber 
was  always  ready,  occupied  about  no  minutes.  When  everything 
went  according  to  plan,  as  turned  out  in  eight  of  the  dives,  there 
were  no  symptoms  except  in  one  case.  One  of  the  divers,  however, 
got  foul  at  a  depth  of  250  feet  and  was  delayed  there  about  three 
hours  before  he  could  be  liberated.  When  he  was  freed  he  came 
up  beyond  the  proper  stopping  places,  disregarding  the  telephoned 
orders.  Possibly  he  was  partly  stupefied  by  the  prolonged  action 
of  the  high  pressure  of  oxygen.  At  forty  feet  from  surface  he 
collapsed.  This  was  about  40  minutes  after  starting  the  ascent. 
He  was  then  pulled  up  to  surface,  where  he  was  still  able  to 
say  a  few  words  before  becoming  unconscious.  His  dress  was 
quickly  ripped  off  and  he  was  hurried  into  the  recompression 
chamber  along  with  the  two  doctors  and  the  other  diver  who  had 
rescued  him.  By  this  time  he  was  black  in  the  face,  his  breathing 
had  ceased,  and  no  pulse  could  be  felt  at  the  wrist.  Artificial  res- 
piration was  at  once  applied,  and  at  the  same  time  the  pressure 
was  run  up  to  75  Ibs.  in  3^/2  minutes,  which  ruptured  both  the 
eardrums  of  one  of  the  doctors.  As  75  Ibs.  pressure  was  reached 
the  patient  suddenly  recovered  and  sat  up,  feeling  all  right  again. 
He  was  then  gradually  decompressed  to  20  Ibs.  in  about  iJ/2 
hours,  but  at  this  point  severe  pain  developed,  so  that  the  pressure 
had  to  be  raised  again.  For  the  next  five  hours  many  attempts  at 
decompression  below  20  pounds  had  to  be  given  up.  At  last  he 
was  very  gradually  decompressed  in  about  3  hours  in  spite  of  the 
pain.  Soon  after  being  taken  from  the  chamber  he  was  in  a  very 
precarious  condition,  with  the  pulse  no  longer  palpable.  In  spite 
of  haematuria,  almost  complete  suppression  of  urine,  extreme 
pain,  and  other  threatening  symptoms,  he  recovered  gradually; 
and  when  it  was  possible  to  examine  his  lungs  he  was  found  to 
have  double  broncho-pneumonia,  the  result,  presumably,  of  the 
very  high  oxygen  pressure,  as  will  be  explained  below.  In  a  few 
weeks  he  had  completely  recovered. 

This  case  shows  clearly  the  efficacy  of  recompression  even  under 

"French,  U.  S.  Naval  Medical  Bulletin,  p.  74,  January,  1916. 


RESPIRATION  353 

conditions  of  apparently  the  most  desperate  character.  It  would 
have  taken  over  four  hours  to  bring  him  up  at  all  safely  by  stage 
decompression,  and  his  blood  was  certainly  full  of  bubbles  before 
he  was  got  into  the  chamber. 

The  difficulty  of  safe  decompression  in  the  chamber  is  one  that 
has  often  been  met  with  before  in  bad  cases.  It  may  be  necessary 
to  keep  a  patient  in  the  chamber  for  24  hours  or  more. 

In  work  in  tunnels  or  caissons  the  pressures  encountered  are 
not  nearly  so  high  as  in  diving  work;  but  the  durations  of  ex- 
posure are  usually  a  good  deal  longer.  Hitherto  the  time  given  to 
decompression  in  the  air  lock  has  hardly  ever  been  sufficient  to 
prevent  symptoms,  though  in  recent  years  it  has  often  been  suffi- 
cient to  prevent  almost  entirely  the  very  dangerous  symptoms 
produced  by  rapid  decompression,  which  leaves  most  of  the  body 
in  a  condition  of  supersaturation  with  nitrogen.  On  this  account 
most  of  the  symptoms  in  tunnel  workers,  etc.,  consist  of  the 
"bends,"  itching  of  the  skin,  etc.,  due  to  bubbles  in  the  tissues 
which  saturate  and  desaturate  very  slowly.  In  divers,  on  the 
contrary,  the  symptoms  met  with  before  stage  decompression  was 
introduced  were  mostly  of  a  far  more  serious  character,  and  due 
to  wholesale  formation  of  bubbles  in  the  blood  and  in  tissues  which 
saturate  and  desaturate  fairly  quickly.  Death  or  more  or  less 
permanent  paralysis  were  therefore  common.  With  shortened 
stage  decompression  it  is  usually  the  less  serious  symptoms  which 
appear  among  divers,  and  if  the  stage  decompression  is  shortened 
these  symptoms  must  be  expected.  It  is  unfortunate  that  stage 
decompression  cannot  be  introduced  in  some  countries  on  account 
of  antiquated  state  regulations  enjoining  decompression  at  a 
constant  rate,  or  even  decompression  starting  very  slowly  and 
increasing  in  rate  as  atmospheric  pressure  is  approached. 

During  decompression,  or  immediately  after  it,  it  is  very  de- 
sirable that  as  much  muscular  work  as  possible  should  be  carried 
out,  so  as  to  increase  the  circulation,  and  therefore  the  rate  of 
desaturation,  over  all  parts  of  the  body,  and  particularly  those 
parts  which,  owing  to  muscular  exertion  during  exposure  to  the 
high  pressure,  may  have  become  saturated  to  a  greater  extent 
than  would  otherwise  be  the  case.  For  this  reason  the  naval  divers 
were  enjoined  to  keep  their  arms  and  legs  moving  as  much  as 
possible  during  the  stoppages  at  each  stage.  Bornstein  has  more 
recently  brought  forward  evidence  collected  at  the  Elbe  tunnel 
works  that  muscular  exertion  just  after  decompression  diminishes 
greatly  the  liability  to  "bends." 


354  RESPIRATION 

It  is  probable  that  the  bubbles  first  formed  in  supersaturated 
blood  and  tissues  are  extremely  small  and  comparatively  harm- 
less. One  can  observe  the  formation  of  these  minute  bubbles  in 
water  which  has  stood  in  a  pipe  under  pressure  in  contact  with 
air.  When  the  tap  is  opened  the  water  comes  out  milky  with 
minute  bubbles,  but  no  large  bubbles  are  present.  The  smallness 
of  the  bubbles  leaves  time  to  deal  with  cases  of  sudden  decompres- 
sion. Thus  a  diver  who  is  blown  up  accidentally  from  a  great 
depth  comes  to  no  harm  if  he  is  sent  down  again  at  once  or  very 
quickly  got  under  high  pressure  in  a  recompression  chamber.  The 
small  bubbles  already  formed  seem  to  go  into  resolution  at  once. 
With  any  delay,  however,  the  bubbles  become  larger  and  more 
difficult  to  redissolve.  In  the  diver  referred  to  above  bubbles  had 
evidently  formed  long  before  he  reached  surface  and  was  recom- 
pressed. 

In  the  case  of  workers  in  tunnels  and  caissons  it  is  practically 
very  difficult,  and  undesirable  in  various  ways,  to  keep  the  men 
very  long  in  an  air  lock  during  decompression.  Another  plan 
seems  much  better,  and  has  been  partially  carried  out  in  recent 
years  in  tunnels  under  construction  at  New  York.9  The  very  high 
pressures  needed  to  keep  the  advancing  face  secure  are  only 
employed  in  a  section  close  to  the  face,  this  section  being  separated 
from  the  rest  of  the  tunnel  by  a  steel  air  dam.  If  the  total  air 
pressure  in  the  advanced  section  is  not  more  than  I J4  times  that  in 
the  rest  of  the  tunnel,  the  men  can  come  through  the  air  lock  with- 
out any  delay.  Let  us  suppose  that  the  excess  pressure  is  35  Ibs. 
at  the  face  and  7.5  Ibs.  in  the  rest  of  the  tunnel.  The  total  atmos- 
pheric pressure  is  thus  50  Ibs.  at  the  face  and  22.5  Ibs.  in  the  rest 
of  the  tunnel.  It  is  evident,  therefore,  that  the  men  who  have  been 
working  at  the  face  can  come  straight  through  either  air  lock, 
even  after  very  long  shifts,  provided  that  they  are  kept  for  a 
sufficient  time  (fully  an  hour)  in  the  low-pressure  part  of  the 
tunnel  before  coming  through  the  second  lock.  If  there  were  ar- 
rangements for  washing,  changing,  and  meals  in  the  low-pressure 
section,  this  hour  could  be  profitably  employed.  A  six-hour  shift 
could  be  worked  at  the  face,  with  an  interval  for  a  meal  in  the 
low-pressure  section,  and  there  would  be  no  blocking  of  the  air 
locks.  The  men  could  also  go  home  at  once,  without  the  risk  of 
symptoms  developing  later.  A  plan  of  this  kind,  modified  to  suit 
the  varying  conditions  at  different  undertakings,  seems  to  afford 
the  best  means  of  solving  the  difficulties  with  air  locks ;  but  exist- 

*  Japp,  Trans.  Intern.  Congress  on  Hygiene,  Section  IV,  Washington,  1912. 


RESPIRATION  355 

ing  state  regulations  might  need  modification  to  enable  the  im- 
provement to  be  introduced.  In  any  case  there  is  now  no  justifica- 
tion for  imperiling  men's  lives  by  methods  of  decompression  which 
are  known  to  give  imperfect  protection. 

At  present  the  tendency  of  the  supervising  medical  officers  is 
to  shorten  the  periods  of  work  at  the  face  under  high  pressure; 
and  of  course  the  period  of  decompression  may  then  be  shortened 
also.  While  this  may  cover  the  physiological  aspects  of  the  prob- 
lem, it  is  evidently  very  uneconomical  as  compared  with  the 
method  above  suggested. 

Not  only  may  increased  partial  pressures  of  nitrogen  and  CO2 
cause  trouble,  but  also  increased  pressure  of  oxygen.  The  poison- 
ous action  of  oxygen  at  high  partial  pressure  was  discovered  by 
Paul  Bert;  and  his  numerous  and  very  thorough  experiments  on 
the  subject  are  described  in  his  famous  book.  There  is  a  popular 
belief,  based  on  the  supposed  similarity  between  life  and  com- 
bustion, that  the  breathing  of  oxygen  at  a  high  partial  pressure 
must  quicken  the  processes  of  life,  and  Paul  Bert's  experiments 
on  the  effects  of  a  high  partial  pressure  seem  to  have  been  begun 
with  the  view  of  testing  this  belief.  He  found  that  when  the  partial 
pressure  of  oxygen  exceeds  three  or  four  atmospheres,  very  re- 
markable tonic  convulsions  are  produced  in  warm-blooded  ani- 
mals, and  they  soon  die.  More  remarkable  still,  perhaps,  their 
body  temperature  falls  in  the  compressed  oxygen,  and  the  con- 
sumption of  oxygen  and  production  of  CO2  are  markedly  di- 
minished. The  oxygen  acts  as  a  poison. 

He  then  extended  his  observations  to  other  forms  of  life  besides 
warm-blooded  animals,  and  proved  conclusively  that  for  life  in 
every  form,  including  the  very  lowest,  oxygen  at  high  pressure 
is  a  poison.  Plants,  infusoria,  and  bacteria  are  killed  just  as 
certainly  as  the  higher  animals.  His  experiments  left  no  doubt  that 
it  is  the  partial  pressure  of  oxygen,  and  not  mere  mechanical 
pressure,  that  matters.  When  air  was  used  instead  of  pure  oxygen, 
the  pressure  required  to  produce  fatal  effects  was  nearly  five  times 
as  great  as  when  pure  oxygen  was  used,  but  the  pressure  of  oxy- 
gen was  the  same.  He  also  found  that  oxygen  pressures  of  less 
than  one  atmosphere  would  kill  or  retard  the  growth  of  various 
small  organisms  of  different  classes  in  the  animal  kingdom,  and  of 
plants ;  and  he  came  to  the  conclusion  that  any  increase  over  the 
normal  oxygen  pressure  of  ordinary  air  is  more  or  less  detrimental 
to  living  organisms  directly  exposed  to  it.  He  had  discovered  a 
biological  fact  of  the  most  far-reaching  significance. 


356  RESPIRATION 

It  is  usually  not  till  the  oxygen  pressure  in  the  air  reaches  more 
than  three  atmospheres  that  warm-blooded  animals  show  marked 
immediate  symptoms  of  oxygen  poisoning.  This  we  can  under- 
stand. The  extra  oxygen  taken  up  in  the  arterial  blood  is  nearly 
all  in  simple  physical  solution,  as  Paul  Bert  showed  by  blood-gas 
analyses  of  the  arterial  blood.  At  three  atmospheres  of  oxygen  the 
blood  will  only  take  up  about  seven  volumes  of  oxygen  in  solution. 
On  the  other  hand,  the  blood  commonly  loses  about  as  much  oxy- 
gen in  its  passage  through  the  capillaries.  It  is  also  indicated 
by  the  results  of  experiments  described  in  Chapter  X,  that  the 
effect  of  the  increased  oxygen  is  to  slow  the  circulation,  so 
that  more  oxygen  than  usual  is  lost.  Hence  the  oxygen  pres- 
sure will  probably  be  very  little  above  normal  in  the  tissues 
or  venous  blood  until  the  oxygen  pressure  in  the  arterial  blood 
is  over  three  atmospheres.  As  was  shown  in  Chapter  VII,  ani- 
mals in  which  the  haemoglobin  has  been  thrown  out  of  action 
by  CO  or  nitrite  poisoning  are  still  a  little  short  of  oxygen  when 
they  are  breathing  oxygen  at  two  atmospheres  pressures.  We  can 
therefore  easily  understand  why  so  high  an  oxygen  pressure  as 
three  or  four  atmospheres  is  needed  before  the  nervous  system 
and  other  tissues  are  markedly  affected  by  the  oxygen. 

In  his  experiments  on  warm-blooded  animals  Paul  Bert  had, 
however,  overlooked  one  thing  which  his  other  experiments  might 
have  led  him  to  look  for.  Although  the  tissues  generally  in  a 
higher  animal  are  protected  from  the  high  pressure  of  oxygen, 
since  they  have  round  them  that  wonderfully  constant  internal 
environment  which  protects  them  from  so  many  variations  in  the 
external  environment,  yet  the  cells  lining  the  air  passages  and 
lungs  are  exposed  to  the  high  oxygen.  It  was  discovered  by  Lor- 
rain  Smith  in  i89910  that  oxygen  at  a  pressure  quite  insufficient 
to  affect  the  nervous  system  appreciably  will,  if  time  is  given, 
produce  fatal  inflammation  of  the  lungs.  The  higher  the  pressure 
of  the  oxygen,  the  sooner  this  appears.  The  lungs  are  filled  with 
exudation,  so  that  they  sink  in  the  fixing  fluid,  a  general  oedema 
similar  to  that  in  phosgene  poisoning  being  produced.  Probably 
the  animals  only  survive  as  long  as  they  do  in  the  compressed 
oxygen  because  they  get  sufficient  oxygen  in  spite  of  the  oedema. 
As  Lorrain  Smith  showed,  the  oedema  protects  them  against  the 
effects  of  very  high  oxygen  pressure  on  the  nervous  system.  At  an 
oxygen  pressure  of  180  per  cent  of  an  atmosphere  (that  to  which 

10  Lorrain  Smith,  Journ.  of  Physwl.,  XXIV,  p.  19,  1899. 


RESPIRATION  357 

the  American  diver  referred  to  above  was  exposed  for  three 
hours)  one  of  the  animals  died  from  lung  inflammation  in  7  hours. 

The  higher  the  oxygen  pressure  the  more  rapidly  was  the  fatal 
inflammation  produced.  The  lowest  oxygen  pressure  at  which  fatal 
pneumonia  was  observed  was  73  per  cent  of  an  atmosphere,  after 
4  days'  exposure.  At  40  per  cent  no  ill  effects  were  observed.  It  is 
evident  from  these  observations  that  when  oxygen  is  used  con- 
tinuously for  therapeutic  purposes  the  percentage  ought  not  to  be 
increased  more  than  is  really  necessary.  A  lung  that  is  already 
inflamed  may  be  extra  sensitive  to  an  unusually  high  oxygen 
pressure.  At  an  oxygen  pressure  corresponding  to  57  fathoms  of 
water  we  found  that  out  of  seven  goats  one  died  in  three  hours 
from  pneumonia,  while  the  others  were  also  affected,  but  re- 
covered on  decompression.  At  an  oxygen  pressure  corresponding 
to  40  fathoms  we  could  not  detect  in  ourselves  any  subjective 
symptoms  during  short  exposures ;  but  quite  probably  such  symp- 
toms might  appear  after  longer  exposure,  and  the  behavior, 
described  above,  of  the  experienced  American  diver  seems  sug- 
gestive of  this. 

Although  oxygen  at  high  pressure  acts  generally  as  a  poison, 
yet  as  shown  in  Chapter  IX,  the  living  swim  bladder  may  contain 
oxygen  at  a  pressure  of  100  atmospheres  without  harm  to  the 
cells  lining  its  walls.  These  cells  are  apparently  "acclimatized"  to 
the  oxygen,  just  as  the  cells  lining  the  stomach  wall  are  acclima- 
tized to  hydrochloric  acid.  It  is  not  improbable  that  the  lungs  are 
capable  of  acquiring  some  degree  of  acclimatization  or  immunity 
to  the  effects  of  a  high  pressure  of  oxygen ;  but  on  this  point  there 
are  as  yet  no  observations. 


CHAPTER  XIII 
Effects  of  Low  Atmospheric  Pressures. 

VERY  low  atmospheric  pressures  are  met  with  on  mountains  or 
high  plateaus  and  in  ascents  by  balloons  or  aeroplanes  to  great 
altitudes.  Mountain  sickness,  one  of  the  characteristic  effects  of 
low  atmospheric  pressures,  was  known  long  before  atmospheric 
pressure  and  the  composition  of  the  atmosphere  were  understood. 
It  was  commonly  attributed  to  poisonous  emanations.  A  good 
account  of  earlier  records  of  it  is  given  by  Paul  Bert.  His  experi- 
ments on  animals  and  men  showed  clearly  that  the  physiological 
effects  produced  by  low  atmospheric  pressure  are  simply  the  re- 
sult of  the  diminished  partial  pressure  of  oxygen.  The  nature  of 
these  effects  and  the  manner  in  which  they  are  produced  have  been 
described  generally  in  Chapters  VI  and  VII  in  connection  with 
the  symptoms  and  causes  of  anoxaemia.  It  remains,  however,  to 
discuss  the  subject  in  detail. 

Although  Paul  Bert's  very  important  conclusion  that  the  physi- 
ological actions  of  oxygen  and  other  gases  depend  on  their  partial 
pressures  has  often  been  referred  to  in  preceding  chapters,  no 
very  definite  account  has  been  given  of  his  experiments.  It  will 
be  convenient  to  summarize  them  here,  and  at  the  same  time  refer 
to  certain  points  on  which  later  investigation  has  thrown  new 
light. 

By  studying  the  conditions  producing  death  in  animals  (chiefly 
sparrows)  confined  in  a  closed  vessel  at  varying  atmospheric  pres- 
sures and  with  varying  compositions  of  the  initial  air  breathed, 
Paul  Bert  proved  that  if  the  pressure  of  oxygen  was  not  sufficiently 
high  to  produce  oxygen  poisoning,  death  was  due  either  to  in- 
creased pressure  of  CO2  or  to  diminished  pressure  of  oxygen.  At 
ordinary  barometric  pressure,  and  with  ordinary  air  inclosed  in 
the  vessel,  death  occurred  when  the  oxygen  percentage  fell  to 
about  3.5.  At  half  the  ordinary  pressure  7.0  was  the  fatal  oxygen 
percentage,  so  that  the  partial  pressure  of  oxygen  was  the  same; 
and  so  on  down  to  pressures  of  a  third  or  even  a  fourth  of  an 
atmosphere.  If  the  vessel  was  filled  with  air  highly  enriched  with 
oxygen  and  the  pressure  was  reduced  to  a  fourth,  or  even  a  tenth, 
the  result  was  the  same  as  regards  the  fatal  partial  pressure  of 


Figure  93. 

Paul  Bert's  apparatus  for  showing  the  effects  of  varying 
low  pressures  of  oxygen  and  CO2.  The  tap  B  is  connected  with 
an  air  pump,  and  D  with  a  bag  of  oxygen  or  nitrogen,  while  C 
connects  with  a  mercury  manometer. 


Figure  94. 

Paul  Bert's  twin  steel  chamber  for  studying  in  man  the 
effects  of  very  low  atmospheric  pressures  with  respiration  of 
oxygen. 


RESPIRATION  359 

oxygen.  On  the  other  hand  if  the  vessel  was  filled  with  the  en- 
riched air  and  left  at  ordinary  barometric  pressure,  death  oc- 
curred when  the  percentage  of  CO2  reached  about  26,  although 
the  oxygen  pressure  was  far  above  the  danger  point ;  and  similarly 
if  the  vessel  was  filled  with  compressed  air  at  a  pressure  not  suffi- 
cient to  cause  oxygen  poisoning.  The  cause  of  death  depended 
simply  on  whether  the  partial  pressure  of  3.5  per  cent  of  an 
atmosphere  of  oxygen  or  26  per  cent  of  an  atmosphere  of  CO2 
was  reached  first.  The  mere  mechanical  pressure  had  no  influence. 
When,  however,  the  partial  pressure  of  oxygen  was  raised  to  the 
dangerous  limits  referred  to  in  Chapter  XII,  death  was  due  to 
oxygen  poisoning,  or  hastened  by  it ;  and  the  results  suggest  that 
increase  of  the  circulation  rate,  owing  to  the  presence  of  CO2,  with 
consequent  increase  of  the  partial  pressure  of  oxygen  in  the  tissues, 
increased  the  poisonous  action  of  the  oxygen,  though  Paul  Bert 
was  unaware  of  the  action  of  CO2  on  the  circulation. 

Figure  93  shows  an  apparatus  used  by  Paul  Bert  for  showing 
that  it  is  the  diminished  pressure  of  oxygen,  and  not  simply  the 
diminished  barometric  pressure,  that  affects  an  animal.  The  fol- 
lowing are  the  notes  of  an  experiment  on  a  sparrow. 

"At  3.20  pressure  reduced  to  250  mm.  in  a  few  minutes.  On 
further  reduction  to  210  mm.  the  animal  turned  round  and  round, 
fell  down,  and  was  at  the  point  of  death.  I  restored  the  normal 
pressure  by  letting  in  air  enriched  with  oxygen ;  the  animal  re- 
covered immediately  and  appeared  lively  and  well.  The  air  in  the 
bell  jar  now  contained  35  per  cent  of  oxygen.  At  3.30  pressure 
reduced  to  180  mm.  when  the  animal  again  became  very  ill.  Pres- 
sure again  restored  to  normal  by  letting  in  oxygen,  when  the  ani- 
mal recovered  at  once.  The  air  now  contained  77.2  per  cent  of 
oxygen.  On  again  reducing  the  pressure  the  animal  did  not  fall 
over  till  100  mm.  pressure  was  reached.  Immediate  recovery  on 
restoring  the  pressure  by  letting  in  oxygen.  The  air  now  contained 
87.2  per  cent  of  oxygen.  On  reducing  the  pressure  to  100  mm.  at 
3.50  the  animal  did  not  seem  at  all  in  danger;  but  at  80  mm.  it  fell 
over  in  a  dying  condition.  It  recovered  at  once  on  letting  in  oxy- 
gen. The  air  now  contained  91.8  per  cent  of  oxygen,  and  at  4.05 
the  pressure  was  reduced  to  75  mm.,  when  the  animal  again  be- 
came very  ill,  so  that  there  was  only  just  time  to  open  the  taps  and 
let  it  recover."  This  experiment  shows  very  clearly  that  in  air 
greatly  enriched  with  oxygen  the  barometric  pressure  could  be 
reduced  to  about  a  third  of  what  was  possible  in  ordinary  air. 

It  was  evident  that  oxygen  could  be  used  to  avert  the  very 


RESPIRATION 

dangerous  effects  of  the  rarefied  air  in  balloon  ascents ;  and  Paul 
Bert  proceeded  to  test  this  on  himself  in  a  steel  chamber  which 
he  had  procured.  The  arrangement  is  shown  in  Figure  94.  In  this 
chamber  he  not  only  studied  in  himself  and  others  the  subjective 
and  other  effects  of  low  barometric  pressure  when  ordinary  air 
was  breathed,  but  also  showed  that  by  breathing  oxygen  all  these 
effects  could  be  prevented  in  man,  down  to  very  low  pressures. 
Figure  95  is  a  diagram  showing  the  variations  of  pressure  in  one 


76    _ 
70  _ 


60  _ 
50  _ 
40  _ 


10-20        30 


Figure  95. 

Tracing  showing  Paul  Bert's  pulse  rate  during  a  decompression  experiment 
in  his  steel  chamber.  Upper  line  =  barometric  pressure  in  centimeters.  Lower 
line  =  pulse  rate.  At  o  the  breathing  of  oxygen  was  begun  and  continued 
till  the  end  of  the  experiment. 

of  his  experiments,  and  the  striking  effect  on  his  pulse  when  he 
began  the  continuous  breathing  of  oxygen.  The  oxygen  abolished 
at  once  the  various  symptoms,  of  which  an  account  was  given  in 
Chapter  VI. 

I  have  frequently  verified  in  steel  chambers,  and  also  when  air 
very  poor  in  oxygen  was  being  breathed,  Paul  Bert's  statements 
as  to  the  effects  of  oxygen.  He  noted  the  sudden  increase  in  ap- 
parent brightness  of  light  and  loudness  of  sounds,  the  return  of 
powers  of  memory  and  of  intellectual  powers,  etc.  As  illustrating 
how  even  one  who  is  perfectly  familiar  with  the  effects  on  vision 
of  rapid  relief  of  anoxaemia  may  be  deceived  by  the  subjective 


RESPIRATION  361 

effect,  I  may  mention  a  recent  personal  experience.  Dr.  Priestley 
and  I  had  gone  to  a  barometric  pressure  of  about  360  mm.  in  a 
steel  chamber  to  test  a  piece  of  apparatus;  and,  being  anxious  to 
test  our  Eustachian  tubes,  we  opened  the  inlet  tap  full,  so  as  to 
raise  the  pressure  to  nearly  normal  within  about  a  minute,  as  in  a 
nose  dive  of  about  18,000  feet.  Our  ears  were  all  right,  but  I  was 
alarmed  to  see  the  filament  of  the  electric  lamp  suddenly  become 
intensely  bright,  as  if  it  were  about  to  fuse ;  and  on  hastily  pushing 
the  door  open  at  the  end  of  the  decompression  I  inquired  what  had 
gone  wrong  with  the  voltage.  The  appearance  was  of  course  only 
subjective.  I  had  forgotten  the  increase  of  oxygen  pressure,  and 
had  only  been  thinking  of  the  mechanical  effect  on  the  eardrums. 

Nothing  in  subsequent  investigation  has  shaken  Paul  Bert's 
conclusions  as  to  the  effects  of  gases  being  dependent  on  their 
partial  pressures,  though  the  scientific  world  has  taken  a  long 
time  to  assimilate  his  reasoning,  so  that  much  of  what  has  been 
subsequently  written  on  the  subject  of  high  and  low  atmospheric 
pressures  has  been  simply  out  of  date.  On  a  number  of  points, 
however,  later  investigations  have  thrown  new  light.  To  take  one 
quite  minor  point  first,  the  action  of  CO  in  air  does  not  depend 
upon  its  partial  pressure,  since  the  higher  the  pressure  of  an 
atmosphere  containing  CO  is  raised  the  more  innocuous  does  the 
CO  become,  from  the  causes  already  discussed  in  Chapters  IV 
and  VII.  But  at  a  constant  partial  pressure  of  oxygen  the  physio- 
logical action  of  CO  depends  upon  its  partial  pressure.  There  may 
be  other  apparent  exceptions  to  Paul  Bert's  rule,  but  we  may  be 
confident  that  they  will  also  turn  out  to  be  only  apparent. 

In  his  experiments  Paul  Bert  took  into  direct  account  only  the 
pressure  of  oxygen  and  other  gases  in  the  inspired  air.  But  we 
have  already  seen  that  what  directly  matters  is  the  gas  pressures 
in  the  alveolar  air.  When  the  barometric  pressure  is  lowered  the 
alveolar  oxygen  pressure  falls  at  a  greater  proportional  rate  than 
the  oxygen  pressure  of  the  inspired  air.  This  is  because,  even 
though  the  breathing  is  increased,  which  would  in  itself  tend  to 
keep  up  the  alveolar  oxygen  pressure,  and  may  nearly  prevent 
the  alveolar  CO2  percentage  from  rising,  the  percentage  of 
aqueous  vapor  is  constantly  rising.  At  a  barometric  pressure  of 
47  mm.  no  air  at  all  would  enter  the  lungs,  since  the  pressure  of 
aqueous  vapor  would  be  47  mm.,  and  the  liquids  of  the  body  would 
from  this  cause  alone  be  just  about  their  boiling  point;  as  a  matter 
of  fact  they  would  boil  at  a  higher  pressure,  as  they  contain  much 
free  CO2.  At  a  pressure  of  100  mm.  in  an  atmosphere  of  pure 


362  RESPIRATION 

oxygen,  the  alveolar  air  in  situ  would  contain  47  per  cent  of  H2O ; 
probably  about  20  per  cent  of  CO2;  and  33  per  cent  of  oxygen, 
with  a  partial  pressure  of  about  4.3  per  cent  of  an  atmosphere  or 
33  mm.  of  mercury.  This  pressure  of  oxygen  is  only  one  twenty- 
third  of  that  in  dry  oxygen  at  atmospheric  pressure,  though  the 
oxygen  pressure  in  the  inspired  oxygen  is  only  reduced  to  a  little 
over  a  seventh. 

It  is  thus  somewhat  remarkable  that  until  extremely  low  baro- 
metric pressures,  such  as  under  100  mm.,  were  reached,  the  deaths 
of  the  animals  from  want  of  oxygen  should  have  coincided  so 
closely  with  a  threshold  oxygen  pressure  in  the  inspired  air.  The 
probable  explanation  of  this  has  already  been  referred  to  in 
Chapter  VI.  With  fall  of  barometric  pressure  the  rate  of  dif- 
fusion in  a  gas  increases  rapidly,  since  the  mean  free  path  of 
each  molecule  before  it  strikes  another  molecule  is  increased.  As 
a  consequence,  the  oxygen  molecules  in  the  neighborhood  of  the 
alveolar  epithelium  reach  it  more  rapidly,  so  that  when  there  is 
scarcity  of  oxygen  the  blood  can  be  more  readily  saturated  to  the 
existing  mean  oxygen  pressure  in  the  alveoli,  or  to  whatever 
higher  oxygen  pressure  can  be  produced  by  active  secretion.  The 
excessive  fall  in  alveolar  oxygen  pressure  at  low  barometric  pres- 
sures is  thus  partially  compensated. 

An  experiment  which  Paul  Bert  describes  (p.  749  of  his  book) 
would  seem  to  confirm  this  explanation.  A  bird  was  placed  in  the 
apparatus  (Figure  93)  and  the  pressure  reduced  to  220  mm.,  at 
which  the  animal  had  severe  symptoms  of  anoxaemia.  The  pres- 
sure was  then  raised  to  normal,  not  with  air,  but  with  nitrogen. 
The  animal  died  almost  at  once,  though  the  partial  pressure  of 
oxygen  was  6  per  cent,  and  the  alveolar  oxygen  pressure  must  have 
been  raised,  owing  to  the  greatly  diminished  proportion  of  aque- 
ous vapor  in  the  alveolar  air  at  normal  barometric  pressure. 

The  importance  of  the  CO2  present  in  the  air  was  not  noticed 
by  Paul  Bert.  In  all  his  experiments  where  the  oxygen  pressure 
of  the  inspired  air  fell  to  about  3.5  per  cent  before  death  there 
was  also  a  considerable  proportion  of  CO2  in  the  inspired  air. 
This  CO2  must  have  stimulated  the  respiration  greatly,  in  the 
manner  already  explained  so  fully,  thus  diminishing  the  fall  in 
alveolar  oxygen  pressure.  The  presence  of  CO2  tends  to  diminish 
the  percentage  saturation  of  the  haemoglobin  in  the  arterial  blood, 
owing  to  the  Bohr  effect  already  referred  to  at  length  in  Chapters 
IV  and  VII,  but  there  is  the  counterbalancing  advantage  that  the 
haemoglobin  holds  on  less  tightly  to  oxygen  in  the  systemic 


RESPIRATION  363 

capillaries.  The  excess  of  CO2  has,  however,  another  quite  dis- 
tinct effect  in  counterbalancing  the  effects  of  the  low  alveolar  oxy- 
gen pressure  :  for  the  circulation  can  increase,  owing  to  thensthnu- 
lus  of  anoxaemia,  without  the  counteracting  effect  due  to  the 
production  of  alkalosis  through  deficiency  of  CO2.  In  this  way  the 
oxygen  pressure  in  the  systemic  capillaries  is  kept  considerably 
higher  than  if  there  were  no  excess  of  CO2  in  the  inspired  air. 

Other  things  being  equal,  the  presence  in  the  inspired  air  of 
a  moderate  proportion  of  CO2  diminishes  the  effects  of  oxygen 
deficiency,  as  can  easily  be  shown  experimentally.  The  CO2,  by 
increasing  the  breathing,  raises  the  percentage  of  oxygen  in  the 
alveolar  air;  and  a  very  small  excess  in  the  alveolar  CO2  pressure 
is  sufficient  to  produce  a  large  effect  on  the  breathing.  There  is 
consequently  a  considerable  increase  in  the  alveolar  oxygen  pres- 
sure. That,  however,  the  effects  of  CO2  in  relieving  anoxaemia 
are  not  simply  due  to  the  increased  oxygenation  of  the  blood  can 
be  shown  most  strikingly  in  CO  poisoning.  A  given  percentage 
of  CO  is  less  poisonous  when  administered  to  an  animal  breathing 
human  expired  air.  As  this  does  not  raise  the  alveolar  oxygen 
pressure,  the  effect  cannot  be  due  to  increased  oxygenation  of  the 
arterial  blood,  and  must  be  put  down  to  increase  in  the  circulation 
rate,  and  consequent  better  supply  of  oxygen  to  the  tissues.  Lor- 
rain  Smith  and  I  found  that  excess  of  CO2  has  no  effect  in  stimu- 
lating oxygen  secretion  by  the  lungs. 

Although  Paul  Bert  had  in  reality  proved  quite  conclusively 
that  the  physiological  effects  of  low  atmospheric  pressures  depend 
on  the  lowering  of  the  oxygen  pressure,  the  theory  was  promi- 
nently brought  forward  by  Mosso  twenty  years  later  that  these 
effects  are  due  primarily  to  excessive  loss  of  CO2  from  the  body, 
or  "acapnia."  Mosso  imagined  that  as  a  physical  consequence  of 
the  low  atmospheric  pressure  more  CO2  than  usual  is  washed  out 
of  the  blood  in  the  lungs,  and  that  this  is  the  cause  of  mountain 
sickness.1  His  physical  chemistry  was  completely  at  fault.  If  the 
volume  of  air  breathed  did  not  alter,  the  partial  pressure  of  CO2 
in  the  alveolar  air  would  remain  the  same,  and  no  more  CO2  would 
be  given  off  at  low  than  at  ordinary  atmospheric  pressure.  Actu- 
ally, however,  there  is  an  excessive  loss  of  CO2  at  low  atmospheric 
pressure,  and  this  is  due  to  the  increased  breathing  caused  by  the 
anoxaemia.  Moreover  we  can,  for  the  reasons  already  explained, 
mitigate  the  anoxaemia  by  adding  a  suitable  proportion  of  CO2 

1  Mosso,  Life  of  Man  on  the  High  Alps  (translation),  London,  1898. 


364  RESPIRATION 

to  the  inspired  air.  Acapnia  may  thus  be  looked  on  as  a  contribu- 
tary  cause  of  the  symptoms,  so  that  at  first  sight  there  seems  to  be 
some  experimental  support  for  Mosso's  theory.  The  acapnia, 
although  most  important,  is,  however,  only  a  secondary  result  of 
the  lowered  oxygen  pressure.  This  aspect  of  the  matter  has  become 
clear  only  recently  through  the  work  of  Kellas,  Kennaway,  and 
myself  (see  Chapter  VI),  and  independently  along  closely  similar 
lines  by  that  of  Yandell  Henderson  and  Haggard.2 

Mosso  held  to  his  acapnia  theory  till  the  time  of  his  death,  and 
it  was  quite  in  vain  that  I  myself  endeavored  to  persuade  him  that 
Paul  Bert  was  right.  "Acapnia"  became  for  a  time  to  many 
physiologists  the  same  sort  of  ignis  fatuus  as  "reduced  alkaline 
reserve"  has  been  in  recent  years.  In  1906,  however,  Zuntz  and 
his  colleagues  placed  the  main  facts  in  true  perspective  in  an  ac- 
count of  investigations  carried  out  at  high  altitudes  in  the  Alps.3 

We  must  now  consider  acclimatization  to  high  altitudes  and 
anoxaemia  caused  in  other  ways.  Paul  Bert  in  his  book  (pp.  336, 
1105)  describes  and  discusses  acclimatization,  though  he  had  not 
himself  studied  it  experimentally.  The  evidence  pointing  to  the 
fact  of  acclimatization  was  clear.  He  suggested  that  the  tissues 
become  gradually  accustomed  to  a  smaller  supply  of  oxygen  in 
the  blood,  and  perhaps  become  more  economical  in  their  use  of 
oxygen.  He  also,  however,  suggests  that  the  oxygen  capacity  of 
the  blood  may  become  increased  at  high  altitudes;  and  this  he 
afterwards  verified  by  actual  examination  of  blood  taken  from 
animals  living  at  high  altitudes.4 

In  1892  Viault  showed  that  the  number  of  red  corpscles  per 
unit  volume  of  blood  is  increased  at  high  altitudes,  and  Miintz 
that  the  percentage  of  iron  is  increased.  Various  subsequent  ob- 
servers-established clearly  the  fact  that  in  animals  and  persons 
living  at  high  altitudes  there  is  an  increase  in  both  the  percentage 
of  haemoglobin  and  the  number  of  blood  corpuscles  in  the  blood. 
By  far  the  most  complete  and  accurate  series  of  observations  on 
the  increase  in  haemoglobin  was  that  carried  out  in  connection 
with  the  Pike's  Peak  Expedition  by  Miss  Fitz Gerald  on  persons 
living  permanently  at  different  altitudes  in  the  Rocky  Mountains 
and  elsewhere  in  America.  Figure  96  shows  graphically  the 
average  results  obtained  at  different  altitudes. 

It  will  be  seen  from  this  figure  that  on  an  average  the  per- 

2  Haggard  and  Henderson,  Journ.  Biol.  Chem.,  XLIII,  p.  15,  1920. 

8  Zuntz,  Loewy,  Miiller,  and  Caspari,  HofienkUma  und  Bergivanderungen,  1906. 

4  Paul  Bert,  Comptes  rendus,  XCIV,  p.  805,  1882. 


RESPIRATION 


365 


centage  of  haemoglobin  varies  inversely  with  the  barometric 
pressure,  and  that  even  quite  small  diminutions  in  barometric  pres- 
sure are  effective  in  causing  a  rise  in  the  haemoglobin  percentage. 
In  different  individuals,  however,  the  effects  on  the  haemoglobin 
percentage  of  a  given  diminution  in  barometric  pressure  vary 


CMWfUfe 


7* 


z«x» 


IVOOO 

rapoo 
12,000 


700         650         600 


Figure  96. 

Average  haemoglobin  percentages  in  persons  living 
permanently  at  different  altitudes  (FitzGerald). 

considerably.  Thus  among  the  persons  acclimatized  on  the 
summit  of  Pike's  Peak  (barom.  453  mm.)  the  rise  in  haemoglobin 
percentage  varied  from  13  to  53  per  cent  of  the  normal.  The  rate 
at  which  the  haemoglobin  percentage  rises  when  a  person  goes  to 
a  high  altitude  varies  also.  In  some  persons  the  rise  is  very  slow; 
and  in  consequence  of  this  some  observers  have  failed  to  detect 
any  rise  on  going  for  a  short  time  to  a  high  altitude. 

As  the  average  rise  in  haemoglobin  percentage  is  appreciable 
with  only  small  increases  of  altitude,  one  would  expect  to  find 
that  with  increase  of  atmospheric  pressure  above  normal  the 
haemoglobin  percentage  would  fall  below  the  normal  value  at 
sea  level.  That  this  is  actually  the  case  was  shown  for  dogs  and  a 
monkey  by  A.  Bornstein,  who  kept  the  animals  under  atmospheric 
pressure  of  about  three  atmospheres  or  2,280  mm.  in  the  Elbe 
tunnel  at  Hamburg  during  its  construction.5  She  found  that  the 

'Adele  Bornstein,  P finger's  Archw.,  138,  p.  609,  1911. 


366  RESPIRATION 

haemoglobin  percentage  and  number  of  red  corpuscles  fell  about 
20  per  cent,  and  that  there  was  no  fall  in  the  case  of  animals  kept 
in  the  tunnel  at  a  place  where  the  atmospheric  pressure  was  not 
increased.  It  appears,  therefore,  that  the  haemoglobin  percentage 
is  regulated  generally  in  relation  to  the  oxygen  pressure  in  the 
arterial  blood,  and  rises  or  falls  according  as  this  pressure  is 
diminished  or  increased. 

It  is  easy  to  see  what  the  physiological  advantage  will  be,  other 
things  being  equal,  of  a  rise  in  the  haemoglobin  percentage.  As 
the  blood  passes  through  the  systemic  capillaries,  its  oxygen  pres- 
sure will  fall  more  slowly  than  usual.  Hence  although  the  arterial 
oxygen  pressure  is  considerably  below  normal,  the  venous  oxygen 
pressure  will  be  much  more  nearly  normal,  so  that  the  lowering 
of  the  oxygen  pressure  in  the  tissues  is  diminshed.  There  may  be 
much  more  of  available  oxygen  in  the  arterial  blood  at  a  high 
altitude  than  at  sea  level,  but  this  in  itself  avails  nothing,  since  it 
is  the  pressure,  and  not  the  quantity,  of  oxygen  in  the  blood  that 
counts.  To  explain  the  beneficial  effects  of  increased  haemoglobin 
percentage  at  high  altitudes  and  in  other  conditions  where  chronic 
arterial  anoxaemia  exists  we  must  consider  the  effects  of  the 
increased  haemoglobin  on  the  oxygen  pressure  in  the  tissues.  At 
the  same  time  we  must  bear  in  mind  the  influence  of  increased 
haemoglobin  percentage  in  diminishing  the  CO2  pressure,  and 
therefore  the  hydrogen  ion  concentration,  in  the  tissues ;  and  this 
brings  us  to  a  second  factor  in  acclimatization. 

In  recent  years  it  has  gradually  been  shown  more  and  more 
clearly  that  at  high  altitudes  the  volume  of  air  breathed  is  in- 
creased and  remains  so  after  acclimatization.  This  was  already 
more  or  less  evident  from  the  measurements  by  Zuntz  and  his 
colleagues  of  the  volume  of  air  breathed  and  respiratory  exchange 
at  high  altitudes,  and,  as  mentioned  in  Chapter  VI,  was  rendered 
quite  clear  by  the  experiments  of  Boycott,  Ogier  Ward,  and 
myself  on  the  alveolar  air  at  low  atmospheric  pressures.  We  drew 
the  conclusion  that  the  blood,  apart  from  the  CO2  contained  in  it, 
becomes  less  alkaline  at  low  atmospheric  pressures,  so  that  less 
CO2  is  needed  to  excite  the  respiratory  center.  This  diminution  in 
the  "fixed"  alkalinity  of  the  blood  was  already  known  through 
titrations.  Barcroft  then  found  on  the  Peak  of  Teneriffe  that  in 
spite  of  the  lowered  pressure  of  CO2  in  the  arterial  blood,  the 
dissociation  curve  of  the  oxyhaemoglobin  of  the  blood  in  presence 
of  the  alveolar  CO2  pressure  remains  sensibly  normal.  This  also 
pointed  in  the  same  direction.  The  phenomena  did  not,  however, 


RESPIRATION  367 

correspond  with  those  accompanying  excess  of  lactic  acid  in  the 
blood,  and  Ryffel  was  unable  to  find  any  such  excess  in  the  blood 
or  urine.  Accordingly  the  conclusion  was  drawn  by  my  colleagues 
and  myself  after  careful  observations  during  the  Pike's  Peak 
Expedition,  that  the  diminution  in  available  alkali  in  the  blood 
must  be  due  to  a  lowering  in  the  level  of  concentration  to  which 
the  kidneys  regulate  the  fixed  alkali  in  the  blood.  We  thought 
that  the  anoxaemia  must  influence  the  kidneys  specifically  in  this 
direction. 

The  Anglo-American  Pike's  Peak  Expedition6  was  planned 
with  the  special  object  of  studying  acclimatization  to  the  oxygen 
deficiency  of  the  air  at  high  altitudes.  We  selected  Pike's  Peak 
(14,100  feet)  because  it  was  possible,  not  only  to  get  apparatus 
and  supplies  to  the  summit  easily  by  the  cogwheel  railway,  but  also 
to  live  there  without  the  disturbing  effects  of  cold  and  hardship. 
We  were  thus  enabled  to  watch  in  ourselves  the  progress,  which 
was  very  striking,  of  acclimatization,  and  to  observe  the  effects  of 
the  rarefied  air  on  the  numerous  unacclimatized  persons  who  came 
up. 

It  is  evident  that  a  simple  increase  in  the  breathing  must 
greatly  diminish  the  arterial  anoxaemia  at  high  altitudes :  for  not 
only  will  the  alveolar  oxygen  pressure  be  increased,  but  in  conse- 
quence of  excessive  removal  of  CO2,  the  haemoglobin  passing 
through  the  lungs  will  combine  more  readily  with  oxygen,  in 
accordance  with  the  discovery,  already  often  alluded  to,  of  Bohr 
and  his  pupils.  It  might  thus  appear  as  if  a  simple  increase  in 
breathing  were  the  natural  adaptive  response  to  the  anoxaemia 
of  high  altitudes  and  other  conditions.  But,  as  already  pointed 
out,  such  a  response  is,  except  for  a  very  short  period,  or  to  a  very 
limited  extent,  prevented,  owing  to  the  effect  of  the  lowered  CO2 
pressure  in  diminishing  the  breathing;  and  an  increased  circula- 
tion rate  (which  would  also  tend  to  diminish  the  fall  of  oxygen 
pressure  in  the  tissues)  is  also  prevented  in  the  same  way.  More- 
over the  increase  in  percentage  saturation  of  the  haemoglobin  in 
the  tissues  is  in  any  case  of  only  limited  advantage,  since,  owing 
to  the  lowered  CO2  pressure,  the  haemoglobin  holds  on  more 
tightly  to  the  oxygen.  Nevertheless  there  will  be  some  increase  in 
breathing  and  circulation  rate;  and  this  will  represent  a  com- 
promise between  the  effects  of  want  of  oxygen  and  of  deficiency 

8  Douglas,  Haldane,  Henderson,  and  Schneider,  Phil.  Trans.  Roy.  Soc.,  B, 
203,  1913- 


368 


RESPIRATION 


DOUGLAS 


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JULY 


HA  LOAN E 


4      &     12     16    20   24    28     /      59 
AUGUST  SEPTEMBER. 


Figure  97. 

Pressure  of  COz  and  oxygen  in  alveolar  air  of  three  members  of  the  Pike's 
Peak  Expedition  at  about  sea  level  (Oxford  and  New  Haven),  at  Colorado 
Springs  (6,000  feet),  and  on  Pike's  Peak  (14,100  feet).  Thick  line  =  alveolar 
COz  pressure,  and  thin  line  =  alveolar  oxygen  pressure.  Interrupted  lines  = 
normal  alveolar  COz  and  oxygen  pressures  at  sea  level. 


RESPIRATION  369 

of  CO2.  It  is  during  this  condition  that  mountain  sickness  is  pro- 
duced. 

In  the  course  of  a  day  or  two,  or  of  several  days,  the  mountain 
sickness  passes  off  if  the  altitude  is  not  too  great ;  but  the  breathing 
is  only  slightly  increased  further,  as  we  found  on  Pike's  Peak 
(Figure  97)  by  analyses  of  the  alveolar  air.  Further  light  on 
acclimatization  was  afterwards  thrown  by  Hasselbalch  and  Lind- 
hard7  in  a  series  of  observations  during  which  they  remained  for 
a  number  of  days  in  a  steel  chamber  at  reduced  pressure.  They 
found  by  direct  measurement  that  after  acclimatization  the  hydro- 
gen ion  concentration  of  the  blood  is  approximately  normal,  thus 
confirming  Barcroft's  conclusions  from  observations  of  the  dis- 
sociation curve  of  the  oxyhaemoglobin  of  the  blood.  They  also 
found  that  the  excretion  of  ammonia  in  the  urine  is  distinctly 
diminished;  and  this  led  them  to  the  conclusion  that  the  very 
slight  acidosis  which  presumably  causes  the  increased  breathing 
is  due  to  diminished  formation  of  ammonia  in  the  body. 

In  a  still  more  recent  investigation8  by  Kellas,  Kennaway,  and 
myself,  we  found  that  on  exposure  to  a  considerable  diminution 
of  atmospheric  pressure  there  is  at  once  a  very  marked  decrease 
in  the  excretion  of  both  acid  and  ammonia  by  the  kidneys.  The 
urine  may  become  actually  alkaline  to  litmus.  These  observations 
threwr  a  new  and  quite  clear  light  on  the  increased  breathing  at 
high  altitudes.  It  became  evident  that  the  increased  breathing  is 
primarily  due  simply  to  the  stimulus  of  anoxaemia.  This  increased 
breathing  not  only  raises  the  alveolar  oxygen  pressure,  but  also 
washes  out  an  abnormal  proportion  of  CO2  and  thus  produces  a 
condition  of  slight  alkalosis,  to  which  the  perfectly  normal  re- 
sponse is  a  diminution  of  ammonia  formation  and  in  the  acidity 
of  the  urine,  as  explained  in  Chapter  VIII.  This  response  tends  to 
continue  until  the  normal  reaction  of  the  blood  is  restored,  owing 
to  reduction  in  the  "available  alkali"  in  the  body.  There  is  no 
acidosis  at  any  stage  of  the  process ;  the  supposed  acidosis  is  only 
the  compensation  of  an  alkalosis.  Nevertheless  the  process  of 
compensation  is  never  quite  complete.  If  it  were  so  the  excretion  of 
ammonia  would  return  to  its  normal  value  on  acclimatization, 
whereas  actually  there  is  still,  as  shown  by  Hasselbalch  and 
Lindhard's  observations,  a  slight  but  distinct  diminution  in  am- 
monia excretion.  Moreover  if  the  compensation  were  complete 

7  Hasselbalch  and  Lindhard,  Biochem.  Zeitschr.,  68,  pp.  265  and  295,  1915; 
and  74,  pp.  i  and  48,  1916. 

8Haldane,  Kellas,  and  Kennaway,  Journ.  of  Physwl.,  LIU,  p.  181,  1919. 


370  RESPIRATION 

there  would  be  no  extra  breathing  caused  by  the  immediate  effect 
of  the  anoxaemia.  Actually  there  is  still  a  slight  amount  of  extra 
breathing  from  this  cause,  since  on  raising  the  alveolar  oxygen 
pressure  there  is  an  immediate,  though  comparatively  slight,  rise 
in  the  alveolar  CO2  pressure,  as  we  found  on  Pike's  Peak  when  a 
mixture  rich  in  oxygen  was  breathed  in  place  of  ordinary  air. 
The  evident  reason  why  the  compensation  does  not  become  more 
complete  is  that  if  it  were  made  more  complete  the  normal  com- 
position of  the  blood  would  be  very  seriously  altered;  and  such 
alterations  tend  to  be  resisted.  The  compensation  thus  represents  a 
compromise. 

A  similar  interpretation  of  the  apparent  slight  acidosis  of  high 
altitudes  was  reached  on  independent  grounds  by  Yandell  Hender- 
son, and  published  shortly  before  our  paper  appeared.9  As  already 
mentioned  in  Chapter  VIII,  he  and  Haggard  made  the  very 
important  discovery  that  with  prolonged  and  very  excessive 
ventilation  of  the  lungs  (thus  producing  great  alkalosis)  the 
available  alkali  or  "alkaline  reserve"  of  the  blood  diminishes 
greatly.  A  similar  diminution  occurs  at  high  altitudes,  and  Hen- 
derson attributed  it  to  the  increased  breathing  produced  by  the 
anoxaemia,  and  was  thus  the  first  to  identify  its  true  nature  as  a 
compensatory  response  to  the  alkalosis  produced  by  the  increased 
breathing. 

It  is  evident  that  the  compensatory  change  in  the  available 
alkali  of  the  blood  and  whole  body  tends  to  make  increased  breath- 
ing possible  with  a  minimum  stimulus  from  actual  anoxaemia. 
The  anoxaemia  tends,  therefore,  to  be  relieved.  In  other  words  a 
process  tending  to  acclimatization  has  occurred.  It  will  be  noted 
that  the  phenomena  have  been  interpreted  on  what  is  usually 
called  a  teleological  basis,  though  no  conscious  adaptation  of 
means  to  end  is  implied,  but  only  a  tendency  of  the  living  body  to 
maintain  its  normal  standards.  The  justification  for  this  mode  of 
interpretation,  and  the  demonstration  that  it  constitutes  the  neces- 
sary scientific  basis  of  physiology,  will  be  postponed  to  the  next 
chapter. 

In  connection  with  the  Pike's  Peak  expedition  Miss  FitzGerald 
carried  out  a  large  series  of  investigations  of  the  alveolar  air  of 
persons  living  permanently,  and  therefore  fully  acclimatized,  in 
towns  and  villages  at  different  altitudes  in  or  near  the  Rocky 
Mountains.  At  a  later  date  further  observations  were  made  at 

9  Yandell  Henderson,  Science,  May  8,  1919;  and  Haggard  and  Henderson, 
Journ.  BioL  Chem.,  XLIII,  p.  15,  1920. 


RESPIRATION 


371 


lower  altitudes  in  South  Carolina.10  The  average  results  are 
shown  in  Figure  98.  The  results  for  men  and  women  are  given 
separately,  as  men  have  a  higher  average  alveolar  CO2  pressure 
than  women,  as  mentioned  in  Chapter  II.  It  will  be  seen  that 
within  the  limits  of  atmospheric  pressure  investigated,  the  aver- 

Cas  pressure  Altitude 

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3OO     ISO      700     650     600     S5O     5OO     4SO     4OO     3SO     SOO     2SO     20O 
Atmospheric  pressure  in  mm. of  mercury. 

Figure  98. 
Alveolar  gas  pressures  in  relation  to  barometric  pressure  or  altitude. 

age  alveolar  CO2  and  oxygen  pressures  fall  proportionally  to 
the  atmospheric  pressure.  To  judge  from  these  results  the  al- 
veolar oxygen  pressure  at  the  height  of  24,600  feet  reached  by  the 

10  FitzGerald,  Phil.  Trans.  Roy.  Soc.,  B,  203,  p.  351  ',  and  Proc.  Roy.  Soc.,  B, 
88,  p.  248. 


372  RESPIRATION 

Duke  of  Abbruzzi's  expedition  would  only  be  about  31  mm.,  and 
the  CO2  pressure  about  2 1  mm.  The  figures,  according  to  a  form- 
ula of  Henderson,11  would  be  oxygen  38  mm.,  and  CO2  15  mm. 

Acclimatization  would  be  a  very  incomplete  process  if  it  de- 
pended solely  on  the  increased  breathing  observed  at  high  alti- 
tudes. In  spite  of  increased  breathing  and  coincident  increased 
saturation  of  the  arterial  blood  owing  to  the  alkalosis  produced, 
there  is  at  first  very  distinct  cyanosis  when  persons  first  go  to  a 
high  altitude.  On  Pike's  Peak  this  was  very  striking,  though  in 
different  persons  the  degree  of  cyanosis  varied  greatly.  The  fact 
that  there  was  so  much  cyanosis  although  the  mean  alveolar  oxy- 
gen pressure  was  about  50  mm. — sufficient  in  presence  of  the 
lowered  alveolar  CO2  pressure  to  saturate  the  haemoglobin  of 
average  human  blood  to  85  per  cent  or  more — is  now  explicable 
by  the  fact  that,  as  explained  in  Chapter  VII,  the  oxygen  pressure 
of  the  mixed  arterial  blood  is  very  appreciably  below  that  of 
the  mixed  alveolar  air,  and  particularly  at  lowered  atmospheric 
pressure.  The  cyanosis  disappears,  however,  after  a  day  or  two, 
or  sometimes  longer,  of  mountain  sickness;  and  in  persons  who 
have  reached  the  high  altitude  by  gradual  stages,  as  in  the  Him- 
alayas, there  may,  apparently,  be  little  or  no  cyanosis,  and  certainly 
no  mountain  sickness.  Among  the  party  of  four  Europeans  with 
the  Duke  of  the  Abbruzzi,  who  gradually  reached  a  height  of 
24,600  feet  in  the  Himalayas,  there  were  no  signs  of  mountain 
sickness  or  undue  exhaustion  at  any  stage.  In  the  account  of  the 
expedition  the  conclusion  was  even  drawn  that  "rarefaction  of 
the  air,  under  ordinary  conditions  of  high  mountains,  to  the 
limits  reached  by  man  at  the  present  day  (a  barometric  pressure 
of  12.28  inches  or  312  mm.)  does  not  produce  mountain  sick- 
ness."12 Mountain  sickness,  and  its  accompaniments  were  con- 
sidered to  be  "in  reality  phenomena  of  fatigue."  The  writer  of 
this  account  was  not  aware  of  the  fact  that  mountain  sickness  is 
easily  produced  in  unacclimatized  persons  without  any  fatigue, 
and  occurs  quite  readily  in  persons  sitting  in  a  steel  chamber  or 
going  by  train  to  a  high  altitude. 

We  may  contrast  the  experience  of  the  Duke  of  Abbruzzi's 
party  with  that  of  Hasselbalch  and  Lindhard  in  their  steel 
chamber.13  They  started  altogether  unacclimatized,  from  the  sea- 
level  air  pressure  of  Copenhagen,  and  only  reduced  the  pressure 

n  Y.  Henderson,  Journ.  BioL  Chem.,  XLIII,  p.  29,  1920. 

12  Filipo  de  Filippi,  Karakouram  and,  Western  Himalaya,  London,   1912. 

18  Hasselbalch  and  Lindhard,  Biochem.  Zeitschr.,  8,  p.  295,  1915- 


RESPIRATION  373 

to  520  mm.,  corresponding  to  a  height  of  11,000  feet;  but  after  a 
few  hours  they  became  so  seriously  affected  by  mountain  sickness, 
with  alarming  cyanosis,  intolerable  headache,  and  feelings  of 
asphyxia  during  the  night,  that  they  had  to  raise  the  pressure  to 
584  mm.  (about  7,000  feet).  Those  ascending  Pike's  Peak  started 
from  a  height  of  about  6,000  feet  and  were  thus  partially  acclima- 
tized; otherwise  their  symptoms  would  doubtless  have  been  more 
marked  than  they  actually  were. 

In  Chapter  IX  the  quantitative  evidence  has  already  been  given 
that  at  high  altitudes  after  acclimatization  the  lungs  actively 
secrete  oxygen  inwards  even  during  rest,  and  that  were  it  not  so 
the  immunity  from  symptoms  of  mountain  sickness  among  ac- 
climatized persons  would  be  totally  unintelligible.  It  only  remains 
to  discuss  here  some  special  points  with  regard  to  oxygen  secre- 
tion. 

The  fact  that  some  time  is  needed  before  oxygen  secretion  is 
effectively  established  at  a  high  altitude,  accords  exactly  with  the 
fact  that  it  takes  a  man  some  time  to  get  his  lungs  and  other  parts 
of  his  body  into  good  physiological  training  for  heavy  muscular 
exertion.  As  was  pointed  out  in  Chapter  IX  there  is  now  very 
clear  evidence  that  in  persons  who  are  in  good  training  oxygen 
secretion  by  the  lungs  plays  a  very  important  part,  whereas  in 
persons  not  in  training  any  secretion  evoked  by  muscular  work  is 
so  feeble  as  to  be  quite  ineffective.  Both  at  high  altitudes  and  in 
training  for  muscular  exertion  the  power  of  secretion  develops 
with  use;  and  development  occurs  in  exactly  the  same  manner 
with  the  exercise  of  all  other  physiological  functions.  At  high 
altitudes  the  stimulus  to  secretion  originates  in  consequence  of  the 
imperfectly  saturated  condition  of  the  arterial  blood;  and  al- 
though after  acclimatization  is  established  the  saturation  of  the 
arterial  blood  with  oxygen  becomes  less  incomplete,  yet  part  of 
the  incompleteness  must  remain;  otherwise  there  would  be  no 
stimulus  to  oxygen  secretion.  In  this  connection  it  should  be  noted 
that  the  arterial  oxygen  pressure  given  by  the  carbon  monoxide 
method  is  the  average  oxygen  pressure  of  the  blood  leaving  the 
alveoli,  and  not  the  oxygen  pressure  of  the  mixed  arterial  blood. 
The  latter  value  is  undoubtedly  a  good  deal  lower  for  the  reason 
already  explained. 

It  has  for  long  been  well  known  to  mountaineers  that  persons 
who  are  in  good  physical  training  for  hard  work  are  far  less 
susceptible  to  mountain  sickness  and  the  other  characteristic  effects 
of  high  altitudes  than  those  who  are  not  in  training.  This  fact  is 


374  RESPIRATION 

the  origin  of  the  common  and  quite  erroneous  opinion  that 
mountain  sickness  is  due  simply  to  exhaustion  and  has  nothing  to 
do  with  barometric  pressure.  It  now  seems  probable  that  in  so 
far  as  acclimatization  is  due  simply  to  increased  power  of  oxygen 
secretion  good  physical  training  in  heavy  exertion  will  do  as 
much  as  continued  exposure  to  the  high  altitude.  As  we  have 
already  seen,  however,  acclimatization  consists  not  merely  in 
increased  power  of  oxygen  secretion,  but  also  in  increased  haemo- 
globin percentage  and  diminution  in  the  available  alkali  in  the 
blood  and  tissues  so  as  to  permit  of  increased  breathing  without 
the  development  of  alkalosis.  It  takes  time  to  bring  about  these 
changes,  and  they  are  not  brought  about  by  training  for  muscular 
work.  The  increased  haemoglobin,  though  it  was  the  first  acclima- 
tization change  to  be  discovered,  is  probably  of  relatively  minor 
importance,  inasmuch  as  recovery  from  mountain  sickness  and 
related  conditions  commonly  occur  before  there  is  any  noticeable 
change  in  the  haemoglobin  percentage.  The  diminution  in  avail- 
able alkali  seems  to  be  much  more  important,  but  the  process  is 
evidently  a  rather  slow  one.  This  is  readily  intelligible  when  one 
considers  the  amount  of  alkali  that  has,  apparently,  to  be  got  rid 
of,  partly  by  excretion  through  the  kidneys,  and  partly  through 
suspension  of  formation  of  ammonia  inside  the  body.  Possibly 
this  part  of  acclimatization  might  be  greatly  hastened  by  the 
administration  of  ammonium  chloride,  the  striking  effects  of 
which  on  the  blood  reaction  were  described  in  Chapter  VIII. 

The  question  of  acclimatization  has  assumed  new  interest,  owing 
to  the  recent  great  extension  of  the  use  of  aeroplanes  at  high 
altitudes.  The  great  advantage  of  good  physical  training  seems 
evident  in  this  connection.  At  the  same  time  it  also  seems  evident 
that  only  a  limited  amount  of  acclimatization  can  be  produced 
either  by  physical  training  or  by  intermittent  exposures  in  aero- 
planes to  low  atmospheric  pressure.  The  limitation  was  distinctly 
evident  in  the  experiments,  mentioned  in  Chapter  IX,  on  the 
degree  of  acclimatization  produced  by  intermittent  exposures  at 
low  pressures. 

We  must  now  discuss  the  symptoms  of  balloonists  and  other 
airmen  at  very  great  altitudes,  and  the  means  of  averting  these 
symptoms.  Enormous  heights  can  easily  be  reached  by  balloons; 
and  quite  recently,  in  consequence  of  the  great  improvements 
during  the  war  in  the  construction  of  aeroplanes  and  their  engines, 
a  height  nearly  as  great  as  those  reached  in  balloons  has  been 
reached  in  aeroplanes.  The  limitation  in  the  heights  to  which  men 


RESPIRATION  375 

have  hitherto  been  able  to  go  is  due  entirely  to  the  physiological 
effects  of  the  reduced  oxygen  pressure  and  the  quite  evident  im- 
perfections of  the  apparatus  used  for  overcoming  these  effects. 

Hot-air  balloons  were  devised  by  the  brothers  Montgolfier,  and 
first  used  at  Paris  in  1783.  Shortly  afterwards  the  well-known 
French  physicist  Charles  invented  the  hydrogen  balloon  and  made 
the  first  ascent  in  1785,  reaching  a  height  of  13,000  feet.  Higher 
ascents  were  soon  after  made,  and  in  1804  another  Frenchman, 
Robertson,  reached  about  26,000  feet  and  was  greatly  affected. 
In  the  same  year  Gay-Lussac  went  to  about  23,000  feet,  but  only 
noticed  slight  effects.  It  seemed  pretty  evident  that  the  limit  of 
safety  was  about  25,000  feet,  but  until  1875  no  balloonist  seems  to 
have  been  actually  killed  by  asphyxiation  due  to  the  rarefied  air. 

In  1862  the  well-known  meteorologist  Glaisher  and  the  bal- 
loonist Coxwell  made  a  famous  very  high  ascent  from  Wolver- 
hampton;  and  Glaisher's  account  of  the  symptoms  observed  was 
very  full  and  valuable.14  In  48  minutes  they  had  reached  a  height 
at  which  the  barometer  stood  at  10.8  inches  (274  mm.).  Glaisher 
found  that  after  this  he  could  no  longer  read  his  thermometer  or 
even  his  watch.  His  last  reading  of  the  barometer  was  9.75  inches 
(248  mm.),  which  he  estimated  as  corresponding  to  29,000  feet.15 
He  then  found  that  his  arms  and  legs  were  paralyzed,  and  then 
his  neck  also,  so  that  he  could  not  hold  up  his  head.  He  could  still 
vaguely  see  Coxwell,  who  had  climbed  up  to  free  the  rope  of  the 
valve,  this  having  got  tangled,  owing  to  rotation  of  the  balloon. 
He  tried  to  speak,  but  could  not,  and  then  suddenly  he  became 
blind.  He  says,  "I  was  still  completely  conscious,  and  my  brain 
was  as  active  as  in  writing  these  lines."  Then  suddenly  he  lost  all 
consciousness  and  appears  to  have  been  unconscious  for  about 
seven  minutes,  during  which  Coxwell  had  fortunately  succeeded  in 
stopping  the  ascent  of  the  balloon  and  bringing  it  down  again  for 
a  considerable  distance.  During  Glaisher's  return  to  consciousness 
he  first  heard  the  words  "temperature"  and  "observation,"  but 
without  seeing  anything.  Then  he  began  to  see  his  instruments 
vaguely,  and  then  other  objects,  and  finally  was  able  to  take  up 
his  pencil  and  continue  his  observations.  The  barometer  was  then 
iiT/2  inches  (292  mm.).  Coxwell  had  never  lost  consciousness. 
He  climbed  down  with  great  difficulty.  Seeing  Glaisher's  condition 
he  tried  to  pull  the  valve  rope,  but  found  that  his  own  arms  were 
now  paralyzed.  He  then,  with  great  presence  of  mind,  got  hold 

14  Glaisher,  Travels  in  the  Air,  London,  1871. 

15  It  is  somewhat  doubtful  whether  the  aneroid  barometer  was  correct. 


376  RESPIRATION 

of  the  rope  with  his  teeth,  and  so  succeeded  in  opening  the  valve 
and  turning  the  balloon  downwards.  By  his  presence  of  mind 
and  determination  he  saved  both  Glaisher's  life  and  his  own. 

The  next  very  high  ascent  was  made  by  the  three  French  sci- 
entists Croce-Spinelli,  Sivel,  and  Tissandier  in  1875,  and  re- 
sulted in  the  death  of  the  two  former.  This  tragic  occurrence 
revealed  in  a  very  clear  manner  the  insidiousness  of  the  onset  of 
dangerous  anoxaemia,  and  the  absolute  necessity  for  taking  the 
most  efficient  means  of  guarding  against  it  at  very  high  altitudes. 
Croce-Spinelli  and  Sivel  had  tried  the  effects  of  oxygen  in  Paul 
Bert's  steel  chamber,  as  well  as  during  a  previous  ascent  to  about 
25,000  feet.  They  were  thus  familiar  with  its  effects.  The  balloon 
was  therefore  provided  with  bags  of  oxygen.  Paul  Bert,  who  was 
away  from  Paris  at  the  time,  had,  however,  written  to  them  that 
the  bags  provided  were  too  small  to  last  for  more  than  a  short 
period.  There  was  not  time,  however,  to  get  larger  ones,  and  for 
this  reason  they  decided  not  to  begin  using  the  oxygen  till  they 
felt  themselves  really  in  need  of  it.  They  reached  a  height  of 
about  24,600  feet  with  the  barometer  at  300  mm.  and  the  balloon 
no  longer  rising.  At  this  point  Sivel  asked  both  his  companions 
whether  they  would  go  higher,  and  on  receiving  their  assent  cut 
the  strings  of  three  bags  of  sand  used  as  ballast.  Figure  99  repre- 
sents the  appearance  of  the  car  of  the  balloon  at  this  point.  In 
Tissandier's  notebook  there  was  the  entry  "1.25,  T  =  — 10°, 
B  =  300.  Sivel  throws  ballast.  Sivel  throws  ballast."  The  writing 
was  scarcely  legible,  and  the  repetition  of  the  words  was  charac- 
teristic of  the  symptoms  of  anoxaemia.  The  balloon  then  rose 
rapidly.  Tissandier  relates  that  he  tried  to  take  up  the  mouthpiece 
of  the  oxygen  tube,  but  his  arms  would  not  move.  Nevertheless 
he  had  no  sense  of  the  danger,  but  felt  happy  that  they  were 
rising.  He  saw  the  barometer  passing  290  and  then  280  and  wished 
to  call  out  that  they  were  at  8,000  meters,  but  his  voice  was 
paralyzed,  and  immediately  afterwards  he  lost  consciousness  and 
did  not  wake  up  till  about  forty  minutes  later. 

The  balloon  was  then  descending  rapidly  and  he  noted  that 
the  barometer  was  at  315.  His  companions  were  still  unconscious. 
He  let  go  some  ballast,  and  shortly  afterwards  Croce-Spinelli 
woke  up  and  let  go  more,  including  the  aspirator.  He  then  became 
unconscious  again.  The  balloon  must  have  gone  up,  and  he  did 
not  wake  up  again  till  an  hour  and  a  quarter  later.  The  balloon 
was  then  at  about  20,000  feet  and  falling  very  rapidly.  Both  Sivel 
and  Croce-Spinelli  were  dead.  Tissandier  had  great  difficulty  in 


Figure  99. 

Sivel,  Tissandier,  and  Croce-Spinelli  in  the  car  of 
the  Zenith.  Sivel  preparing  to  cut  the  strings  of  the 
ballast  bags  at  300  mm.  barometric  pressure.  Croce- 
Spinelli  with  the  bubbling  arrangement  for  breathing 
oxygen  in  his  hand.  Tissandier  reading  the  barometer. 
The  oxygen  bags  are  seen  above  the  car,  and  the  re- 
versible aspirator  fixed  to  the  basket  work. 


RESPIRATION 


377 


letting  go  the  anchor  and  landing  safely,  but  succeeded.  Figure 
100  indicates  diagrammatically  the  course  of  the  balloon.  The 
maximum  height  was  given  by  an  automatic  recorder. 


9000 


3000 


2000 


MMW/////,'.  y////////////^^^^ 


L0ire  ri.-.!      '  C<ron 

Chotfouroux  INOHC 

Figure  100. 
Diagram  of  the  voyage  of  the  Zenith,  April  15,  1875. 

It  was  clear  that  all  three  had  been  paralyzed  before  they  tried 
to  breathe  the  oxygen.  Doubtless  they  were  all  convinced  that 
they  felt  all  right  and  in  full  possession  of  all  their  faculties.  The 
feeling  of  self-confidence  seems  always  to  be  present  in  conditions 
of  gradually  advancing  anoxaemia.  I  have  experienced  it  myself, 
not  only  in  steel  chambers,  but  also  in  experimental  CO  poisoning; 
and  the  conviction  that  one  is  fully  competent  is  still  present  in 
spite  of  the  knowledge  that  this  conviction  may  be  a  gross  illusion. 
A  man  who  is  grossly  intoxicated  by  alcohol  has  just  the  same 


378  RESPIRATION 

insane  confidence  that  he  is  all  right.  At  very  high  altitudes  in 
balloons  or  aeroplanes  it  is  imperative  that  oxygen  should  be 
breathed  continuously. 

For  about  twenty  years  after  the  accident  just  described  no 
further  very  high  ascents  in  balloons  seem  to  have  been  attempted. 
The  next  high  ascents  were  made  in  Germany,  starting  with  an 
ascent  by  Berson  and  Gross  to  26,000  feet  in  1894.  Berson  alone 
then  reached  a  height  of  30,000  feet;  and  finally  in  1901  Berson 
and  Siiring  reached  about  36,000  feet  (n,ooo  meters),  with  a 
barometric  pressure  of  1 80  mm.  In  all  these  ascents  oxygen  was 
used,  without  which  they  would  have  been  quite  impossible ;  but 
at  the  end  of  the  last  ascent  both  Berson  and  Siiring  became  un- 
conscious, though  fortunately  not  before  the  former  had  pulled 
the  valve  rope  and  thus  turned  the  balloon  downwards.  Berson 
had  the  cooperation  of  the  Austrian  physiologist,  von  Schrotter, 
and  the  latter  in  his  book  describes  not  only  the  ascents,  but 
various  preliminary  experiments  in  a  steel  chamber  and  experi- 
mental ascents  in  which  he  made  physiological  observations.  Von 
Schrotter  had  thoroughly  grasped  Paul  Bert's  work  and  was  not 
misled  by  the  mistaken  opposition  of  some  physiologists  to  the 
oxygen  theory.16 

Berson  and  Siiring  used  steel  oxygen  cylinders  from  which  a 
constant  stream  of  oxygen  came  to  them  through  a  tube  which 
they  could  hold  in  the  mouth.  The  cylinders  were  a  great  improve- 
ment on  the  bags  used  by  Croce-Spinelli  and  his  companions,  but 
in  other  respects  the  arrangement  was  very  imperfect,  as  von 
Schrotter  pointed  out.  With  any  increase  of  breathing  the  volume 
of  oxygen  supplied  became  insufficient,  so  that  only  a  mixture  of 
air  and  oxygen  was  breathed,  the  air  being  taken  in  through  the 
nose  or  by  opening  the  mouth.  Moreover  it  required  constant 
attention  to  inspire  through  the  mouth,  even  if  the  supply  of 
oxygen  was  adequate.  It  was  no  wonder,  therefore,  that  first 
Siiring  and  then  Berson  was  overcome. 

In  one  of  the  ascents  by  Berson  and  von  Schrotter  liquid  air 
was  tried  for  the  first  time.  It  failed,  partly  because  there  was 
no  proper  means  of  gasifying  as  much  of  the  liquid  as  they  re- 
quired, and  partly  because  the  oxygen  percentage  in  the  gasified 
liquid  air  was  not  high  enough.  Cailletet  had,  however,  already 
indicated  a  method  of  controlling  the  gasification,  and  this  method 
in  an  improved  form  was  extensively  used  by  the  Germans  during 

18  Von  Schrotter,  Der  Sauerstoft  in  cLer  Prophylaxte  und  Therapie  der  Luft- 
druckerkrankungen,  1906. 


RESPIRATION 


379 


the  war — for  instance  in  the  very  high  flights  needed  for  bombing 
London.  It  is  of  course  necessary  to  use  liquid  oxygen.  Simple 
liquid  air  would  evidently  be  quite  useless ;  but  if  ordinary  liquid 
air  is  allowed  to  evaporate  for  a  sufficient  time  the  nitrogen  dis- 
tills off,  leaving  a  residue  very  rich  in  oxygen.  It  was  this  residue 
that  was  employed  by  von  Schrotter  and  Berson. 

To  improve  upon  the  simple  tube  hitherto  used,  von  Schrotter 
strongly  recommended  the  use  of  a  face  piece,  and  figures  the 
first  form  used.  The  face  piece  covers  both  mouth  and  nose,  and 
the  oxygen  passes  into  it  through  a  tube  in  a  constant  stream. 
This  arrangement  was  introduced  for  aeroplanes  before  the  war, 
and  is  now  extensively  used.  The  airman  can  inspire  or  expire 
air  freely,  but  always  receives  a  certain  amount  of  oxygen,  and  has 
not  to  think  of  his  breathing.  The  amount  of  oxygen,  whether  from 
a  steel  cylinder  or  from  a  Dewar  flask  of  liquid  oxygen,  can  be 
adjusted  according  to  the  height,  but  it  is  simpler  to  arrange  for 
a  constant  supply  which  is  sufficient,  or  more  than  sufficient,  up 
to  a  certain  height.  About  half  the  oxygen  is  wasted,  as  it  reaches 
the  face  piece  during  expiration.  This  waste  can  be  prevented  by 
an  arrangement  similar  to  that  already  described  (Figure  49)  in 
connection  with  the  administration  of  oxygen  to  patients.  Priest- 
ley and  I  found  in  steel-chamber  experiments  that  with  this  ar- 
rangement about  I  liter  a  minute  (measured  at  sea-level  pressure) 
was  sufficient  up  to  a  height  of  28,000  feet  during  rest ;  but  at  least 
2  liters  were  needed  for  such  exertions  as  an  aeroplane  observer 
or  pilot  has  to  make.  With  the  light  steel  cylinders  or  large  Dewar 
flasks  now  in  use  the  waste  of  oxygen  with  the  ordinary  arrange- 
ment of  mask  does  not  greatly  matter,  however. 

A  height  as  great  as  Berson  and  Siiring  reached  in  a  balloon 
has  quite  recently  (March,  1920)  been  reported  as  reached  in  an 
aeroplane  by  Major  Schroeder  of  the  American  Army  Air  Service, 
who,  however,  also  became  unconscious,  and  had  a  very  narrow 
escape.  How  it  was  that  the  oxygen  supply  became  insufficient  in 
this  remarkable  ascent  has  not  yet  been  reported. 

The  heights  hitherto  attained  represent  by  no  means  the  limit 
which  Paul  Bert's  experiments  on  animals  indicated  when  pure 
oxygen  is  breathed.  All  that  is  shown  by  them  is  that  the  oxygen 
supply  was  insufficient.  At  36,000  feet  a  man  breathing  pure 
oxygen  would  be  quite  unaffected  by  the  altitude.  The  barometric 
pressure  is  about  1 80  mm.  In  the  alveolar  air  there  would  be  a 
pressure  of  47  mm.  of  aqueous  vapor  and  40  mm.  of  CO2-  Hence 
(by  difference)  there  would  be  93  mm.  of  oxygen  pressure;  and  in 


380  RESPIRATION 

the  rarefied  air  this  would  certainly  suffice  to  saturate  the  arterial 
blood  to  the  same  extent  as  at  sea  level.  At  140  mm.  of  barometric 
pressure  there  would  still  be  at  least  53  mm.  of  alveolar  oxygen 
pressure;  and  it  is  probable  that  marked  symptoms  of  oxygen 
shortage  would  only  begin  to  appear  at  pressures  below  this.  At 
100  mm.  they  would  become  urgent  in  unacclimatized  persons. 
At  80  mm.  Paul  Bert's  animals  were  at  the  point  of  death. 

It  is  difficult  to  see  how  the  addition  of  CO2  to  the  inspired 
oxygen  could  be  of  any  service,  although  at  moderate  diminutions 
of  pressure  CO2  is  of  considerable  service,  as  already  pointed 
out.  When  pure  oxygen  is  breathed  it  is  impossible  to  raise  the 
alveolar  CO2  pressure  without  lowering  the  alveolar  oxygen  pres- 
sure; and  at  very  low  barometric  pressures  every  millimeter  of 
alveolar  oxygen  pressure  counts.  Moreover  rise  of  alveolar  CO2 
pressure  would,  on  account  of  the  Bohr  effect,  tend  of  itself  to 
diminish  the  percentage  saturation  of  the  arterial  blood  with 
oxygen  and  thus  counteract  any  advantage  gained  by  increased 
rate  of  circulation.  Aggazotti  has  shown17  that  when  animals  are 
placed  in  oxygen  containing  a  considerable  percentage  of  CO2 
they  are  capable  of  withstanding  extremely  low  pressures;  but 
the  same  was  found  by  Paul  Bert  when  the  atmosphere  was  one 
of  pure  oxygen.  Aggazotti  himself  reached  the  very  low  pressure 
of  120  mm.  in  a  steel  chamber  while  breathing  oxygen  with  CO2 
added. 

To  make  it  safe  to  go  much  above  30,000  feet  it  would  be 
necessary  to  have  an  apparatus  which  made  it  certain  that  the 
wearer  always  breathed  pure  oxygen,  or  at  any  rate  oxygen  not 
mixed  with  any  other  gas  than  CO2.  An  ordinary  mine-rescue 
apparatus  with  the  usual  constant  oxygen  supply  of  about  2  liters 
per  minute  (measured  at  ordinary  atmospheric  pressure)  would 
secure  this  result  with  a  very  moderate  expenditure  of  oxygen. 
Care  would,  however,  be  necessary  to  insure  that  both  the  purifier 
and  the  oxygen  supply  worked  properly  at  the  low  temperature 
and  pressure  met  with  at  very  high  altitudes.  With  a  larger  con- 
sumption of  oxygen  an  apparatus  could  be  made  to  work  safely 
without  a  purifier.  If  it  were  required  to  go  much  above  40,000 
feet,  and  to  a  barometric  pressure  below  130  mm.,  it  would  be 
necessary  to  inclose  the  airman  in  an  air-tight  dress,  somewhat 
similar  to  a  diving  dress,  but  capable  of  resisting  an  internal  pres- 
sure of  say  130  mm.  of  mercury.  This  dress  would  be  so  arranged 

"Aggazotti,  Arch.  ital.  de  Biologie,  XLVI,  1905. 


RESPIRATION  381 

that  even  in  a  complete  vacuum  the  contained  oxygen  would  still 
have  a  pressure  of  1 30  mm.  There  would  then  be  no  physiological 
limit  to  the  height  attainable. 

The  problem  of  going  to  very  high  altitudes  with  an  oxygen 
apparatus  is  similar  to  that  of  using  a  self-contained  breathing 
apparatus  in  mine  air  which  is  either  intensely  poisonous  from 
the  presence  of  CO  or  H2S,  or  contains  little  or  no  oxygen. 
This  problem  has  been  solved  successfully,  so  that  teams  of 
miners  have  worked  daily  for  weeks  or  months  at  places  a  long 
distance  from  where  there  was  any  oxygen  in  the  air.  The  same 
care  as  is  needed  and  actually  taken  in  the  case  of  the  mining 
apparatus  is  even  more  necessary  in  the  case  of  airmen  at  great 
altitudes,  but,  owing  to  prevailing  ignorance,  has  not  yet  been 
applied.  At  36,000  feet,  for  instance,  with  the  barometric  pres- 
sure at  a  quarter  the  normal,  an  airman  breathing  pure  oxygen 
would  be  much  nearer  danger  if,  owing  to  some  accident,  he  took 
several  breaths  of  the  surrounding  air,  than  a  miner  using  a  self- 
contained  breathing  apparatus  would  be  if  he  took  several  breaths 
of  an  atmosphere  of  fire  damp.  The  miner  would  have  in  his 
lungs  to  start  with  a  pressure  of  700  mm.  of  oxygen,  whereas  the 
airman  would  have  only  about  90  mm.  To  the  airman  at  very 
high  altitudes  it  is  therefore  specially  necessary  to  have  an  ap- 
paratus which  is  perfect  in  its  action  and  is  used  with  all  the 
precautions  which  our  existing  physiological  knowledge  shows 
to  be  necessary. 


CHAPTER  XIV 
General  Conclusions. 

ON  looking  back  at  the  results  reached  in  successive  chapters  of 
this  book  certain  points  of  general  physiological  significance 
emerge.  The  present  chapter  will  be  devoted  to  their  discussion. 

It  is  evident  that  within  the  limits  of  health  the  breathing 
represents  the  lung  ventilation  required  to  keep  the  reaction 
and  the  pressure  of  oxygen  in  the  blood  supplying  the  re- 
spiratory center  constant  within  certain  narrow  limits,  and  that 
the  breathing  increases  or  diminishes  in  accordance  with  the 
quantity  of  air  needed  to  produce  this  effect.  The  "chemical"  and 
"nervous"  stimuli  acting  on  the  respiratory  center  cooperate  in 
bringing  about  the  constancy.  The  circulation  is,  in  the  main, 
similarly  regulated  so  as  to  maintain  a  normal  reaction  and 
oxygen  pressure  in  each  of  the  various  organs,  although  other 
factors  may  also  determine  the  local  circulation  rate  to  some 
extent. 

The  quantity  of  respired  air  required  to  keep  the  arterial  blood 
normal  varies  with  the  very  variable  consumption  of  oxygen  and 
output  of  carbonic  acid  by  the  whole  of  the  living  tissues.  In 
different  individual  parts  of  the  body  the  variations  in  consump- 
tion of  oxygen  and  output  of  carbonic  acid  are  still  more  striking; 
and  meeting  these  variations  there  are  equally  striking  variations 
in  the  local  circulation  rates. 

What  is  regulated  by  the  breathing  and  circulation  is  not  pri- 
marily the  consumption  of  oxygen  and  formation  of  carbonic  acid, 
but  the  partial  pressures,  or  diffusion  pressures,  of  these  sub- 
stances. If  their  diffusion  pressures  become  more  than  slightly 
abnormal  the  result  is,  not  a  mere  slowing  or  quickening  of  physio- 
logical activity,  but  totally  abnormal  activity  and  abnormal  change 
in  structure.  What  is  immediately  effected  is  the  maintenance  of 
these  pressures.  The  supply  of  oxygen  and  removal  of  carbonic 
acid  are  such  as  to  keep  them  approximately  steady.  We  have  also 
seen  that  it  is  simply  as  an  acid  that  carbonic  acid  is  of  physio- 
logical importance,  so  that  in  reality  a  normal  reaction,  or  normal 
diffusion  pressure  of  hydrogen  and  hydroxyl  ions,  and  not  merely 
a  normal  diffusion  pressure  of  carbonic  acid,  is  maintained. 


RESPIRATION  383 

After  Harvey's  discovery  of  the  circulation  and  Lavoisier's 
discoveries  with  regard  to  respiratory  exchange  and  animal  heat, 
many  physiologists  looked  upon  circulation  and  breathing  as 
processes  which  primarily  determine  and  regulate  tissue  activity. 
We  can  trace  this,  for  instance,  in  the  physiological  ideas  of 
Descartes  and  Liebig,  and  in  ideas  still  to  some  extent  prevalent 
as  to  the  causes  of  respiratory  exchange,  secretion,  and  growth. 
Closer  examination  has  shown  that  breathing  and  circulation  are 
responses  to  tissue  activity,  and  do  not  primarily  determine  it. 

Another  tendency  has  been  to  regard  the  nervous  system  as  the 
primary  autonomous  regulator  of  breathing  and  circulation.  The 
evidence  brought  forward  above  has  shown,  however,  that  the 
regulative  influence  of  the  nervous  system  is  not  autonomous, 
but  dependent  on  conditions  of  environment  determined  mainly 
by  varying  tissue  activity. 

In  his  "Le9ons  sur  les  phenomenes  de  la  vie"  (p.  121)  Claude 
Bernard  drew  the  conclusion  that  "all  the  vital  mechanisms, 
varied  as  they  are,  have  only  one  object,  that  of  preserving  con- 
stant the  conditions  of  life  in  the  internal  environment"  (the 
blood).  No  more  pregnant  sentence  was  ever  framed  by  a  physi- 
ologist, and  the  long  series  of  investigations  described  in  the 
present  book  may  be  regarded  as  an  attempt  to  follow  out  in 
regard  to  blood  reaction  and  oxygen  supply  the  line  which 
Bernard  indicated.  Physiological  activities  can  in  one  sense  be 
summed  up  in  the  "preservation  of  the  conditions  of  life  in  the 
internal  environment,"  with  consequent  maintenance  of  normal 
structure.  In  another  sense,  however,  physiological  activity  is 
constantly  disturbing  the  internal  environment.  What  is  actually 
maintained  is  a  dynamic  balance  between  the  disturbing  and 
restorative  activities.  The  order  displayed  in  this  dynamic  balance 
is  the  order  of  biology. 

In  view  more  particularly  of  Paul  Bert's  experimental  demon- 
stration that  the  physiological  action  of  gases  dissolved  in  the 
blood  depends  on  the  pressures  which  they  exert  in  the  surround- 
ing atmosphere — that  is  to  say  on  their  vapor  pressures — we  may 
conclude  that  it  is  the  diffusion  pressures  of  substances  dissolved 
in  the  blood  that  correspond  to  Bernard's  "conditions  of  life."  This 
definition  includes  temperature :  for  diffusion  pressure,  other 
things  being  equal,  varies  as  the  absolute  temperature  and  indeed 
gives  us  our  measure  of  temperature,  since  the  expansion  of  gases 
or  liquids,  by  which  we  measure  temperature,  depends  on  increase 
of  diffusion  pressure. 


384  RESPIRATION 

It  is  a  familiar  fact  that,  apart  from  the  contained  gases,  the 
composition  of  blood  plasma  is  extremely  constant.  The  varied 
experiments  initiated  by  Ringer  and  carried  forward  by  many 
other  observers  indicate  directly  the  physiological  importance  of 
the  various  salts  or  their  ions  which  are  present  in  blood  plasma, 
and  render  intelligible  the  exactitude  with  which  their  concentra- 
tions are  regulated  by  the  kidneys.  The  facts  collected  in  the  pres- 
ent book  show  that  also  as  regards  hydrogen  and  hydroxyl  ions 
and  free  oxygen  the  composition  of  the  blood  plasma  in  contact 
with  any  particular  part  of  the  tissues  is,  and  must  be,  very  con- 
stant, and  is  kept  so  by  regulation  of  breathing,  circulation,  kidney 
excretion,  and  other  physiological  activities.  Thus  oxygen  and 
hydrogen  and  hydroxyl  ions  take  their  place  in  a  strict  quantita- 
tive sense  beside  the  salts,  proteins,  sugar,  etc.,  which  help  to 
make  up  Bernard's  "conditions  of  life." 

We  also  now  know  that  what  is  called  the  osmotic  pressure  of 
blood  plasma  is  so  constant  that  the  existing  methods  of  measur- 
ing it  by  depression  of  freezing  point  or  vapor  pressure  are  too 
coarse  for  the  detection  of  such  differences  as  are  constantly  oc- 
curring during  life  and  evoking  the  ordinary  physiological  re- 
sponses of  the  kidneys  and  other  organs.  Osmotic  pressure  de- 
pends, however,  as  already  mentioned  (Chapter  VIII)  on  the 
difference  between  the  diffusion  pressure  of  a  solvent  in  a  solution 
and  in  the  pure  solvent.  It  is  thus  in  reality  the  diffusion  pressure 
of  water  in  the  blood  that  is  maintained  so  constant.  The  diffusion 
pressure  of  water  can  thus  be  placed  in  the  same  category  as  that 
of  other  substances  among  Bernard's  "conditions  of  life."  The 
experiments  of  Priestley  and  myself1  on  the  excretion  of  water 
by  the  kidneys  show  that  the  regulation  by  the  kidneys  of  the 
diffusion  pressure  of  water  in  the  blood  is  comparable  in  its  ex- 
treme delicacy  to  the  regulation  of  blood  reaction. 

As  a  general  rule  salts,  water,  and  various  other  substances 
present  in  blood  plasma  are  to  only  a  very  small  extent  used  up 
by  or  given  off  from  the  tissues.  Hence  in  the  case  of  most 
tissues  it  would  require  only  a  very  slow  circulation  to  keep  the 
concentrations  of  these  substances  constant  in  the  blood,  pro- 
vided that  the  temperature  was  constant.  If,  however,  the  circu- 
lation were  much  slower  than  it  is,  and  if  this  were  rendered 
possible  by  the  provision  in  the  blood  of  much  greater  capacity 
for  carrying  oxygen  and  CO2  as  easily  dissociable  compounds, 

1Haldane  and  Priestley,  Journ.  of  Physiol.,  L,  p.  296,  1916;  Priestley,  Ibid,.* 
L,  p.  304,  1916. 


RESPIRATION  385 

the  even  regulation  of  temperature  in  the  body  would  apparently 
become  impossible,  and  in  other  ways  the  physiological  inter- 
connection between  different  parts  of  the  body  would  be  less  close 
and  rapid. 

Although  water  and  salts  are  by  ordinary  measurements  neither 
absorbed  by  nor  given  off  from  most  living  tissues,  it  is  evident 
that  this  only  means  that  passage  of  them  into  the  tissues  is  bal- 
anced by  passage  outwards.  A  liquid,  like  a  gas,  consists  of  mole- 
cules in  rapid  movement  and  diffusing  in  all  directions.  We  can- 
not follow  the  movements  of  individual  molecules,  and  can  only 
detect  gain  or  loss  when  either  the  relative  proportions  of  different 
kinds  of  molecules  alter,  or  the  total  number  increases  or  dimin- 
ishes. When  as  many  molecules  or  ions  of  any  one  substance 
are  passing  in  as  are  passing  out  there  appears  to  be  neither  ab- 
sorption nor  giving  off  of  the  substance.  Nevertheless  there  is 
continuous  molecular  or  ionic  exchange,  and  the  blood  is  in  con- 
stant and  active  physiological  connection  with  the  surrounding 
tissues.  As  is  shown  by  the  immediate  effects  of  altering  the 
diffusion  pressure  of  salts,  water,  or  other  blood  constituents,  the 
exchange  of  molecules  continues  during  life,  whether  a  tissue  is 
"active"  or  "resting."  In  reality  there  is  constant  physiological 
activity,  and  the  conventional  sharp  distinction  between  conditions 
of  rest  and  activity  is  extremely  misleading. 

From  the  standpoint  of  physical  chemistry  life  depends  upon 
the  maintenance  of  a  balance  of  molecular  exchanges  between  the 
tissue  elements  and  their  environments.  If  the  balance  is  disturbed, 
so  that,  for  instance,  too  many  or  too  few  water  molecules  or 
potassium,  calcium,  or  sodium  ions  are  passing  from  the  blood 
to  the  tissues  or  vice  versa,  life  is  imperiled.  The  case  is  exactly 
similar  with  oxygen  molecules,  or  with  hydrogen  and  hydroxyl 
ions.  If  the  oxygen  diffusion  pressure  in  the  plasma  falls  so  low 
that  the  proportion  of  oxygen  molecules  passing  in  is  abnormally 
low  as  compared  with  that  passing  out  there  is  physiological  dis- 
turbance; and  similarly,  as  shown  in  Chapter  XII,  when  too  much 
oxygen  is  passing  inwards. 

Hitherto  the  supply  of  oxygen  has  not  been  regarded  from  this 
standpoint.  It  has  been  generally  assumed  that  the  oxygen  mole- 
cules are  all  passing  in  one  direction  and  that  an  irreversible  re- 
action occurs  in  the  living  tissues  by  which  oxygen  is  fixed  so  that 
no  free  oxygen  molecules  are  returned  to  the  environment.  The 
facts  indicating  the  great  importance  of  a  certain  definite  dif- 
fusion pressure  of  oxygen  in  the  immediate  environment  of  the 


386  RESPIRATION 

tissue  elements  are  inconsistent  with  this  view.  The  experimental 
evidence  shows  that  we  must  place  the  diffusion  pressures  of  oxy- 
gen and  carbonic  acid  in  exactly  the  same  category  as  the  diffusion 
pressures  of  water,  salts,  and  other  dissolved  constituents  of  blood 
plasma.  This  means  that  oxygen  molecules  are  constantly  passing 
both  outwards  and  inwards,  although  in  ordinary  tissues  more 
are  passing  inwards.  It  is  only  in  oxygen-secreting  tissues  that  we 
find  that  on  one  side  of  the  secreting  membrane  oxygen  molecules 
are  passing  more  readily  outwards,  and  only,  so  far  as  yet  known, 
in  the  green  parts  of  plants  and  in  the  presence  of  light  that  free 
oxygen  is  on  all  sides  passing  more  readily  outwards  from  living 
tissue  elements  than  inwards.  But  even  in  green  plants,  as  Paul 
Bert  showed,  a  considerable  diffusion  pressure  of  oxygen  is  neces- 
sary for  life. 

We  can  thus  compare  living  structures  to  dissociable  chemical 
molecules  and  particularly  molecules  which,  like  haemoglobin, 
form  molecular  compounds  only  capable  of  existing  in  so  far  as 
rate  of  loss  is  balanced  by  rate  of  gain.  We  must,  however,  assume 
that  the  dissociation  and  association  are  taking  place  simultane- 
ously in  many  different  directions,  corresponding  to  the  many 
different  substances  present  in  the  blood  plasma  and  necessary 
for  life.  We  have  also  to  remember  that  although  the  individual 
tissue  elements  are  all  in  connection,  direct  or  indirect,  with  the 
blood  plasma,  they  are  also  in  connection  with  one  another,  and 
that  this  implies  additional  conditions  of  stability  in  connection 
with  which  molecular  or  ionic  gains  and  losses  are  balanced 
against  one  another. 

It  is  clear  that  the  stability  in  respect  of  one  kind  of  molecular 
gain  or  loss  determines  the  stability  in  respect  of  others.  Thus  a 
small  deficiency  of  oxygen  molecules,  or  a  small  excess  of  hydro- 
gen ions,  in  the  blood  plasma,  disturbs  the  equilibrium  of  the 
receptor  elements  in  the  respiratory  center  and  leads  to  the  extra 
molecular  discharges  which  show  themselves  in  increased  activity 
of  the  center.  Disturbances  in  other  directions  of  the  composition 
of  the  blood  plasma  have  similar  results,  though  the  receptors 
are  specially  sensitive  to  changes  in  reaction  or  deficiency  in  oxy- 
gen pressure.  We  can  interpret  similarly  the  mode  of  action  of 
various  stimuli  acting  on  living  tissues,  including  what,  for  want 
of  more  intimate  knowledge,  we  call  mechanical  stimuli.  Hence  we 
are  led  to  the  conception  of  a  living  organism  as  the  seat  of  a  vast 
system  of  mutually  dependent  reversible  chemical  reactions.  For 
irreversible  chemical  reactions  physiology  has  but  little  use. 


RESPIRATION  387 

The  mechanistic  interpretation  of  life  fails  to  take  account  of 
the  mutual  dependence  throughout  a  living  organism  of  these 
reactions.  When  we  remove  any  part  of  the  organism  from  its 
physiological  connection  with  its  environment  including  the  other 
parts,  we  at  the  same  time  necessarily  alter  its  reactions  and  the 
stability  of  its  living  structure.  Hence  we  cannot  investigate  an 
organism  as  we  investigate  the  parts  of  a  machine  by  taking  them 
apart  and  ascertaining  the  properties  and  structure  of  each  sepa- 
rate part.  The  same  criticism  applies  to  what  may  be  called  the 
''hormone"  theory  of  the  interconnection  between  the  parts  of  an 
organism.  On  this  theory  the  interconnection  is  brought  about 
through  the  existence  of  special  chemical  messengers,  or  "hor- 
mones," produced  in  minute  quantities  by  each  organ,  and  bring- 
ing about  specific  excitatory  effects,  resulting  in  coordinated 
action.  The  hormone  theory,  like  the  mechanistic  theory,  tacitly 
assumes  that,  apart  from  the  influence  of  hormones,  and  of  the 
central  nervous  system,  each  part  of  an  organism  leads  an  inde- 
pendent existence.  The  truth  is  that  every  substance  which  enters 
into  the  life  processes  of  any  part  of  an  organism  is  as  much  a 
hormone  as  any  other  such  substance.  Water,  for  instance,  is  the 
most  abundant  constituent  of  the  body,  and  a  very  minute  excess 
in  the  diffusion  pressure  of  water  in  the  blood  excites  very  striking 
reaction  in  the  kidneys.  This  minute  excess  seems,  therefore,  to 
act  as  a  hormone,  just  as  a  minute  deficiency  in  alkalinity  or  in 
oxygen  pressure  acts  as  a  hormone  to  the  respiratory  center. 
Since,  however,  water,  hydrogen  and  hydroxyl  ions,  and  oxygen 
are  influencing  the  body  continuously,  the  conception  of  them  as 
hormones,  acting  only  occasionally,  is  quite  misleading.  The 
physiological  interconnection  between  different  parts  of  the  body 
is  continuously  in  existence  and  far  more  intimate  than  is  assumed 
by  either  the  ordinary  mechanistic  theory  or  the  hormone  theory. 

In  the  case  of  chemical  compounds  which  we  ordinarily  regard 
as  being  stable  in  their  existing  environment,  and  not  in  a  constant 
state  of  association  and  dissociation,  it  is  well  known  that  the 
particular  nature  of  one  of  the  atomic  linkings  may  make  a  great 
difference  to  the  others.  Thus  the  general  properties  of  an  or- 
ganic compound  may  be  greatly  changed  when  a  hydrogen  atom 
is  replaced  by  a  chlorine  atom  or  a  methyl  radicle.  We  have  also 
seen  in  Chapter  IV  how  in  oxyhaemoglobin  the  affinity  of  the 
haemochromogen  part  of  the  molecule  for  oxygen  is  affected  by 
changes  in  environment  affecting  primarily  another  part  of  the 
molecule.  From  the  point  of  view  of  our  present  chemical  knowl- 


388  RESPIRATION 

edge  there  is  thus  nothing  new  in  principle  in  the  fact,  character- 
istic of  physiological  reactions,  that  any  particular  reaction  is  de- 
pendent upon  the  whole  life  of  an  organism.  Nevertheless  it  is  just 
here  that  we  strike  the  dividing  line  between  the  physical  sciences 
and  biology. 

A  physiological  reaction,  when  we  examine  it  closely,  is  always 
found  to  depend  on  a  vast  number  of  conditions  of  structure  and 
environment.  It  is  true  that  under  "normal  conditions"  the  same 
stimulus  will  produce  the  same  reaction  again  and  again;  but 
when  we  inquire  what  normal  conditions  represent  we  find  some- 
thing which  is  indefinitely  complex  from  the  physical  and  chemi- 
cal standpoint.  We  have  only  to  alter  slightly  the  diffusion  pres- 
sure of  one  or  other  of  the  many  substances,  only  partially  known, 
in  the  blood  plasma,  in  order  to  obtain  a  quite  different  reaction. 
For  instance  a  given  fall  in  the  diffusion  pressure  of  oxygen  fails 
to  excite  the  respiratory  center  if  the  hydrogen  ion  concentration 
of  the  blood  is  very  slightly  below  normal;  and  if  the  calcium 
ion  concentration  were  a  little  above  or  below  normal  there  would 
doubtless  also  be  an  abnormal  result.  The  presence  of  a  trace  of 
ether  or  morphia,  or  probably  of  numerous  other  substances, 
affects  the  center  in  a  similar  manner.  The  excitability  of  a  tissue 
to  any  given  physical  or  chemical  stimulus  may  thus  vary  in- 
definitely under  slightly  different  conditions. 

If  we  attempt  to  investigate  physiological  phenomena  from  the 
standpoint  merely  of  physics  or  chemistry,  we  are  thus  at  once 
landed  in  confusion.  In  investigating  ordinary  physical  or  chemi- 
cal phenomena,  we  can  examine  one  by  one  the  parts  or  units 
we  are  dealing  with  and  ascertain  their  properties,  so  that  from 
the  empirical  knowledge  thus  gained  we  can  predict  what  will 
result  when  they  act  on  one  another.  In  other  words  we  can  give 
physical  and  chemical  explanations  of  their  mutual  action.  But 
when  we  attempt  to  do  this  as  regards  the  actions  on  one  another 
of  the  parts  of  an  organism,  or  of  the  organism  and  its  environ- 
ment, we  are  met  by  the  difficulty  that  we  cannot  ascertain  the 
structures  and  properties  of  any  of  the  separate  parts,  since  their 
structures  and  properties  actually  depend  on  the  existing  physio- 
logical relations  of  the  parts  and  environment  to  one  another.  The 
relativity  of  the  phenomena  confronts  us  at  every  turn  in  the 
attempt  to  reach  physical  and  chemical  explanations  of  physio- 
logical reactions. 

Up  to  a  certain  point  we  can,  it  is  true,  understand  living  organ- 
isms mechanically.  We  can,  for  instance,  weigh  and  measure  them 


RESPIRATION  389 

and  their  parts,  and  investigate  their  mechanical  and  chemical 
properties.  This  enables  us  to  predict  certain  points  in  their  be- 
havior, as  shown,  for  instance,  in  Chapters  IV  and  V.  But  when  we 
look  more  closely  it  becomes  quite  evident  that  the  knowledge 
we  gain  from  mere  physical  and  chemical  examination  hardly 
touches  any  fundamental  physiological  problem.  We  cannot  es- 
cape from  the  relativity  of  the  phenomena  we  are  dealing  with. 

The  only  way  of  real  advance  in  biology  lies  in  taking  as  our 
starting  point,  not  the  separated  parts  of  an  organism  and  its 
environment,  but  the  whole  organism  in  its  actual  relation  to 
environment,  and  defining  the  parts  and  activities  in  this  whole  in 
terms  implying  their  existing  relationships  to  the  other  parts  and 
activities.  We  can  do  this  in  virtue  of  the  fundamental  fact,  which 
is  the  foundation  of  biological  science,  that  the  structural  details, 
activities,  and  environment  of  organisms  tend  to  be  maintained. 
This  maintenance  is  perfectly  evident  amid  all  the  vicissitudes  of 
a  living  organism  and  the  constant  apparent  exchange  of  material 
between  organism  and  environment.  It  is  as  if  an  organism  al- 
ways remembered  its  proper  structure  and  activities ;  and  in  repro- 
duction organic  "memory,"  as  Hering  figuratively  called  it,2  is 
transmitted  from  generation  to  generation  in  a  manner  for  which 
facts  hitherto  observed  in  the  inorganic  world  seem  to  present  no 
analogy.  We  can  discover  and  define  more  and  more  clearly  by 
investigation  these  abiding  details  of  structure  and  activity,  dis- 
tinguishing accidental  appearances  from  what  is  really  main- 
tained; and  this  process  of  progressive  definition  is  the  work  of 
the  biological  sciences. 

If  we  look  back  on  the  general  outcome  of  the  investigations 
summarized  in  this  book,  it  is  evident  that  the  progress  made  has 
consisted  in  distinguishing  underlying  identity  of  activity  amid 
superficial  appearances  which  at  first  sight  present  confusion.  In 
the  second  and  third  chapters  it  was  shown  that  behind  the  ir- 
regularities of  ordinary  breathing  the  mean  pressure  of  CO2  in 
the  alveolar  air  is  maintained  steady  within  narrow  limits  for 
each  individual ;  and  in  a  later  chapter  it  was  more  definitely 
shown  that  this  implies  a  similar  steadiness  in  the  CO2  pressure  of 
the  respiratory  center.  In  Chapter  VIII  this  conclusion  is  widened 
by  the  evidence  that  CO2  pressure  is  only  important  as  an  index 
of  blood  reaction,  and  that  it  is  blood  reaction,  and  not  mere  pres- 
sure of  CO2,  that  is  kept  so  constant  by  the  breathing.  In  Chap- 

2  E.  Hering,  Memory  as  a  Generalized,  Function  of  Organized  Matter  (1870). 
English  Translation,  Chicago,  1913. 


390  RESPIRATION 

ters  VI,  VII,  and  IX  it  is  shown  that  there  is  similar  maintenance 
of  the  pressure  of  oxygen  in  the  blood,  and  in  Chapter  X  evidence 
is  collected  that  the  circulation  is  so  regulated  as  to  keep  both  the 
oxygen  pressure  and  the  reaction  very  nearly  steady  in  each  part 
of  the  body.  Chapter  XIII  deals  with  the  manner  in  which  the 
body  adapts  itself  to  an  abnormal  atmosphere  in  accordance  with 
the  principles  laid  down  in  preceding  chapters. 

It  is  thus  with  the  dominant  fact  that  in  various  definite  re- 
spects the  internal  environment  of  the  living  body  tends  to  be 
maintained  very  steady  that  the  investigations  brought  together 
in  the  preceding  chapters  have  mainly  dealt.  This  dominant  fact 
is  what  makes  a  scientific  treatment  possible  in  actual  practice, 
and  furnishes  us  with  principles  by  means  of  which  we  can  predict 
physiological  responses  and  at  the  same  time  gain  a  practical  con- 
trol of  the  living  body,  such  as  is  required  in  medicine  and  sur- 
gery. 

When  we  find  that  a  certain  characteristic  structure  and  internal 
environment  exists  within  a  living  organism,  we  have  discovered 
what  at  first  sight  appears  to  be  a  fact  capable  of  definition,  though 
not  of  explanation,  in  physical  and  chemical  terms.  Thus  the 
"normal"  diffusion  pressures  of  substances  present  in  the  blood 
are  simply  diffusion  pressures  which  we  can  measure  and  define, 
one  by  one,  in  ordinary  physical  and  chemical  terms.  But  when 
something  occurs  which  tends  to  alter  one  of  the  diffusion  pres- 
sures, or  to  disturb  the  structure,  we  realize  more  fully  the  real 
nature  of  what  is  maintained  in  a  living  organism :  for  the  altera- 
tion is  not  entirely  prevented,  but  met  by  active  readjustment  of 
such  a  character  that  what  we  easily  recognize  as  organic  identity 
is  maintained.  If,  for  instance,  the  oxygen  pressure  in  the  air 
inspired  is  lowered,  a  quantitatively  corresponding  lowering  in 
the  oxygen  pressure  of  the  blood  passing  through  the  tissues  is 
prevented  by  increased  breathing,  oxygen  secretion  by  the  alveolar 
epithelium,  and  rise  in  the  haemoglobin  percentage.  At  the  same 
time  other  disturbances  which  would  naturally  result  from  these 
changes  are  met  by  diminution  in  the  "available"  alkali  in  the 
blood,  increase  in  blood  volume,  and  so  on.  A  widespread  re- 
adjustment of  physiological  activities  and  of  blood  composition 
has  thus  occurred,  but  with  the  result  that  the  more  fundamental 
diffusion  pressures  of  oxygen,  hydrogen  and  hydroxyl  ions,  etc., 
have  altered  only  very  little,  and  in  this  slight  alteration  they  have 
held  together  as  a  whole.  The  oxygen  pressure,  for  instance,  is 
not  restored  at  the  expense  of  hydrogen-ion  pressure  or  excessive 


RESPIRATION  391 

work  of  the  heart  or  lungs.  What  is  maintained  in  the  tissue  en- 
vironment is  oxygen  pressure  in  its  organic  relations.  The  rela- 
tivity to  one  another  of  the  phenomena  of  life  stands  out  clear  in 
this  maintenance  of  organic  identity. 

In  the  course  of  biological  investigation  we  meet  on  all  hands 
with  similar  examples  of  maintenance  and  reestablishment  of 
organic  identity ;  and  the  existence  of  this  actively-maintained 
identity  is  the  scientific  basis  of  practical  medicine  and  surgery. 
But  for  the  fact  that  functional  as  well  as  structural  compensation 
is  constantly  occurring,  not  only  under  ordinary  physiological 
conditions,  but  also  in  cases  of  injury  by  disease  or  accident,  and 
that  by  observation  and  experiment  we  can  learn  to  understand, 
predict,  and  aid  it,  physicians  and  surgeons  would  be  absolutely 
helpless.  Neither  scientific  biology  nor  scientific  medicine  could 
be  based  on  the  ordinary  working  hypotheses  of  physics  and  chem- 
istry, since  these  hypotheses  furnish  no  sufficient  means  of  under- 
standing and  predicting  biological  phenomena.  Biologists,  physi- 
cians, and  surgeons  are  not,  and  never  will  be,  simply  chemists 
and  physicists. 

In  physiology  we  are  always  dealing  with  responses  to  immedi- 
ate stimuli ;  but  the  responses  are  evidently  determined  in  relation 
to  the  maintenance  of  organic  identity.  They  are  organic  responses, 
and  are  simply  rendered  unintelligible  when  by  the  common  con- 
fusion in  thought  running  through  so  much  of  the  present  teaching 
of  physiology  they  are  represented  as  examples  of  mechanical 
determination.  Such  expressions  as  the  "mechanism"  of  respira- 
tion, or  secretion,  or  of  maintenance  of  the  internal  environment 
generally,  are  examples  of  this  confusion.  On  closer  examination 
all  the  assumed  mechanical  reactions  turn  out  to  be  expressions  of 
the  organic  maintenance  which  is  the  subject  matter  of  the  bio- 
logical sciences. 

Biology  must  take  as  its  fundamental  working  hypothesis  the 
assumption  that  the  organic  identity  of  a  living  organism  actively 
maintains  itself  in  the  midst  of  changing  external  appearances. 
This  identity  is  not  physical  identity  nor  identity  of  form  or 
chemical  composition,  but  something  which  we  can  perceive  and 
trace  by  exact  quantitative  investigation  just  as  readily  and  ex- 
actly as  we  perceive  and  trace  physical  identity  in  what  we  inter- 
pret as  the  inorganic  world.  The  science  which  traces  this  organic 
identity  is  biology.  Anatomy  or  morphology  traces  it  as  regards 
structure,  and  physiology  as  regards  activity.  But  since  organic 
structure  is  only  the  outcome  or  expression  of  ordered  activity, 


392  RESPIRATION 

and  organic  activity  only  the  activity  which  expresses  itself  in 
organic  structure,  the  two  branches  of  biology  are  in  reality  one, 
and  we  may  look  forward  to  a  time  when  the  present  wholly 
artificial  and  sterilizing  separation  of  them  will  disappear  along 
with  the  disappearance  of  the  mechanistic  theory  to  which  the 
separation  is  due. 

The  true  scientific  procedure  of  biology  is  different  from  that 
of  the  physical  sciences.  In  physics  and  chemistry  the  procedure 
employed  is  to  ascertain  the  properties  of  the  separate  units  of 
matter  and  energy  with  which  it  is  assumed  that  these  sciences 
deal.  Thus  from  the  properties  and  movements  of  the  parts  of  a 
material  system  such  as  a  machine  we  can  predict  its  behavior 
and  can  design  and  control  machinery.  From  the  properties  and 
movements  of  the  molecules  in  a  given  quantity  of  gas  we  can 
predict  its  behavior.  From  the  properties  of  the  atoms  of  carbon 
and  other  elements  we  can  predict  the  existence  and  many  of  the 
properties  of  carbonaceous  and  other  compounds.  But  we  cannot 
predict  in  this  way  the  behavior  of  a  living  organism.  The  re- 
lationships, for  instance,  into  which  the  carbon  atoms  as  inter- 
preted by  chemistry  enter  within  living  organisms  show  them- 
selves to  be  too  complex  and  changeable,  so  that,  apart  from  the 
biological  method  of  treatment,  we  should  be  totally  at  a  loss.  In 
the  physical  sciences  we  are  looking  at  collections  of  units,  each  of 
which  is  looked  at  from  the  outside.  In  biology  we  are  looking  at 
each  unit  from  the  inside,  and  biological  results  afford  abundant 
justification  for  this  method  of  looking  at  them. 

It  may  appear  at  first  sight  as  if  the  biological  method  were 
unscientific,  and  the  claim  may  be  made  that  it  ought  to  be,  and 
ultimately  must  be,  possible  to  advance  in  biology  by  the  method 
of  the  physical  sciences.  This  claim  must  now  be  examined  care- 
fully. 

The  reason  why  the  physical  or  chemical  method  of  treatment 
is  so  unsatisfactory  in  biology  is  that  in  connection  with  living 
organisms  the  properties  of  the  parts  show  peculiarities  which  we 
do  not  meet  with  in  what  we  distinguish  as  the  inorganic  world. 
Let  us  take  the  case  of  nitrogen  atoms.  When  nitrogen  is  pres- 
ent as  a  gas  at  an  ordinary  temperature  the  properties  of  its  mole- 
cules seem  to  be  very  simple  for  all  practical  purposes.  The  mole- 
cules simply  repel  one  another  when  they  meet,  or  when  they 
encounter  molecules  of  other  gases;  and  the  kinetic  theory  of 
gases,  based  on  this  simple  assumption,  enables  us  to  predict  with 
the  greatest  accuracy  the  behavior  at  ordinary  temperatures  and 


RESPIRATION  393 

pressures  of  a  mass  of  gaseous  nitrogen  or  of  a  mixture  of  nitrogen 
with  another  gas.  But  if  we  raise  the  temperature  sufficiently,  and 
hydrogen  or  oxygen  is  present, the  nitrogen  combines  with  it,  form- 
ing ammonia  or  oxides  of  nitrogen.  The  properties  of  nitrogen 
have  thus  shown  themselves  to  be  more  complex  than  the  simple 
kinetic  theory  of  gases  assumed.  But  from  the  atomic  theory  as  ap- 
plied in  chemistry,  and  the  theory  of  valencies,  we  can  still  predict 
more  or  less  successfully  the  composition  of  the  compounds  formed 
by  the  nitrogen.  Most  of  their  special  properties  have  to  be  ascer- 
tained by  experiment;  but  once  ascertained  they  can  be  used  for 
the  purpose  of  predicting  how  these  compounds  will  behave  un- 
der quite  new  conditions.  It  is  exactly  the  same  when  we  come  to 
the  complex  proteins  and  other  organic  nitrogenous  compounds 
which  can  be  separated  from  the  bodies  of  organisms.  So  long  as 
they  are  separated  from  living  organisms  we  can  investigate 
them  just  as  we  investigate  other  chemical  compounds,  and  they 
present  no  real  obstacle  to  such  investigation. 

The  obstacle  appears  whenever  the  assumed  chemical  mole- 
cules are  participating  in  the  life  of  an  organism.  Their  proper- 
ties seem  then  to  become  fluid  and  dependent  from  moment  to 
moment  on  the  position  of  each  molecule  relatively  to  multitudes 
of  other  molecules  of  the  most  diverse  kinds.  We  consequently 
cannot  trace  the  individual  molecules,  and  cannot  tell  whether  or 
how  they  are  in  combination  with  other  molecules.  They  seem  to 
develop  a  quite  indefinite  potentiality  of  exhibiting  unsuspected 
properties. 

Now  this  fact  shows  us  clearly  that  the  simple  atoms  and  mole- 
cules of  physics  and  chemistry  are  only  a  sensuous  illusion :  for, 
behind  the  supposed  simplicity,  indefinite  potentialities  are  hid- 
den and  actually  show  themselves  in  connection  with  the  phenom- 
ena of  life.  The  properties  and  activities  of  what  we  call  atoms 
or  molecules  are  in  reality  a  function  of  their  relations  to 
other  atoms  and  molecules ;  and  this  fact,  which  is  not  at  once  evi- 
dent in  what  we  call  the  inorganic  world,  becomes  perfectly  evi- 
dent in  biological  phenomena.  Organic  individuality  is  something 
very  evident  to  our  perception,  and  has  thus  the  same  claim  to 
reality  as  inorganic  structure;  but,  from  a  purely  physical  and 
chemical  point  of  view,  living  structure  and  activity  constitute  not 
merely  a  molecular  flux  like  that  of  a  river  or  a  flame,  but  an 
altogether  undefinable  flux — undefinable  because  we  cannot  define 
the  molecular  changes.  It  is  biological  and  not  physical  or  chemi- 
cal structure  and  activity  which  biological  investigation  enables 


394  RESPIRATION 

us  to  define  more  and  more  accurately  and  fully.  Only  when  an 
organism  is  dead  do  we  seem  to  have  before  us  a  physical  and 
chemical  complex. 

Those  who  insist  that  physiological  activity  must  in  reality  be 
physical  and  chemical  change  have  to  answer  a  previous  ques- 
tion as  to  the  justification  for  the  assumption  of  physical  and 
chemical  reality.  The  molecules,  atoms,  and  electrons  of  the 
physical  sciences  seem  real  enough  so  long  as  we  confine  ourselves 
to  the  superficial  aspect  of  reality  which  is  dealt  with  by  the 
physical  sciences;  but  it  is  the  same  reality  that  is  dealt  with  by 
biology,  and  we  reach  a  different  interpretation  of  it  through  the 
study  of  biological  phenomena.  In  this  interpretation  the  self- 
existent  individuality  of  atoms  and  molecules  fades  away  in  rela- 
tivity. 

The  modern  world  has  become  so  accustomed  to  the  material- 
istic assumption  which  identifies  the  mechanical  interpretation  of 
reality  with  actual  reality  that  in  spite  of  the  existence  of  biology, 
psychology,  ethics,  religion,  and  philosophy  it  is  difficult  at  pres- 
ent to  obtain  even  a  hearing  for  the  view  that  physical  reality  rep- 
resents no  more  than  superficial  sensuous  appearance.  By  the  help 
of  various  makeshift  hypotheses  such  as  those  of  vitalism  or 
animism,  the  real  philosophical  problem  as  to  the  ultimate  validity 
of  the  physical  interpretation  of  reality  has  been  evaded  for  the 
time.  But  these  evasions  cannot  satisfy  us,  and  the  problem  comes 
up  in  a  clear-cut  and  definite  form  in  connection  with  the  relation 
of  biology  to  physics  and  chemistry.  The  facts  dealt  with  in  the 
latter  sciences  present  us  with  one  interpretation  of  "reality,"  or 
"nature,"  and  those  dealt  with  by  the  former  present  us  with  a 
different  one. 

Which  of  the  two  interpretations  corresponds  more  closely  to 
actual  reality?  There  appears  to  me  to  be  no  doubt  that  the  biolog- 
ical interpretation  does.  The  progress  of  the  physical  sciences 
has  taught  us  that  the  gases,  liquids,  and  solids  which  to  super- 
ficial examination  appeared  to  be  continuous  and  inert  substances 
are  not  only  discrete  but  made  up  of  molecules  in  continuous 
relative  movement,  and,  in  the  case  at  least  of  solids  and  liquids, 
continuously  affecting  one  another's  movements  and  properties. 
We  now  know  also  that  atoms  themselves  are  systems  of  still  more 
elementary  units  moving  relatively  to  one  another  at  enormous 
velocities,  and  that  in  chemical  combination,  and  even  in  solution 
or  what  we  call  simple  mechanical  interaction,  these  systems  are 
modified,  as  shown,  by  electrical  phenomena.  The  chemist  can 


RESPIRATION  395 

determine  with  great  apparent  accuracy  the  proportions  of  hydro- 
chloric acid  and  water  in  an  aqueous  solution.  In  actual  fact  there 
may  be  practically  no  hydrochloric  acid  molecules  present  and  far 
fewer  simple  molecules  of  water  than  would  appear  from  the 
analysis,  since  the  molecules  are  partly  ionized  and  partly  com- 
bined with  one  another  in  various  forms.  Consequently  the  re- 
sults of  the  analysis  represent  only  a  "practical"  convention,  how- 
ever useful  this  convention  may  be.  In  reality  the  properties 
of  both  the  conventional  hydrochloric  acid  and  the  conven- 
tional water  depend  on  the  particular  conditions  existing  in  the 
solution.  But  the  inquiry  can  be,  and  has  been,  pushed  still  further. 
At  first  sight  it  seems  as  if,  in  whatever  way  the  molecules  of 
water  and  hydrochloric  acid  may  be  split  up  or  combined,  the 
mass  present  is  something  independent  of  changeable  relations. 
But  here,  again,  the  progress  of  physical  science  has  indicated 
that  even  the  mass  of  what  is  present  depends  upon  relative  move- 
ment, and  finally  that  absolute  movement  in  empty  space  is  a 
conception  to  which  no  experimentally  verifiable  meaning  can  be 
attached. 

We  only  deceive  ourselves  when  we  imagine  that  in  physical 
and  chemical  investigation  we  are  free  of  relativity.  Behind 
all  the  superficial  appearances  of  a  "real"  physical  world,  rela- 
tivity finally  appears;  but  in  biological  phenomena  the  relativity 
is  always  evident  and  prominent,  and  precludes  the  possibility  of 
even  a  conventional  physical  and  chemical  interpretation  of 
the  observed  facts.  In  frankly  accepting  relativity,  and  framing 
her  interpretations  on  a  principle  based  upon  it,  biology  comes  a 
step  nearer  to  actual  reality  than  the  physical  sciences. 

It  has  come  to  be  popularly  believed  that  if  we  knew  enough 
of  the  physics  and  chemistry  of  what  occurs  in  a  living  organism 
biological  interpretation  could  be  reduced  to  physical  and  chemi- 
cal interpretation.  Though  the  attempts  to  give  physical  and 
chemical  interpretations  of  biological  phenomena  have  never  been 
successful,  and  their  failure  in  detail  is  becoming  more  and  more 
evident  with  the  progress  of  both  physiological  and  physical  in- 
vestigation, labored  endeavors  are  still  made  to  teach  physiology 
and  represent  the  growing  body  of  physiological  knowledge  in 
physical  and  chemical  terms.  The  investigations  described  in  the 
present  book  illustrate  the  fruitlessness  of  these  attempts.  In  the 
phenomena  connected  with  breathing  we  are  everywhere  dealing 
with  organic  regulation — in  other  words  with  the  manifestations 
amid  superficial  changes  which  at  first  sight  puzzle  and  confuse 


396  RESPIRATION 

us,  of  organic  identity.  It  is  the  same  in  connection  with  the  phe- 
nomena of  circulation,  excretion,  absorption,  and  other  physio- 
logical activities.  I  wish  to  claim  very  definitely  that  in  dealing 
with  biological  phenomena  and  putting  her  questions  to  Nature, 
biology  must  use  her  own  working  hypothesis,  and  not  those  of  the 
physical  sciences. 

The  organic  regulation  which  we  find  everywhere  in  a  living 
organism  does  not  represent  something  imposed  from  without  on 
the  processes  occurring  in  the  organism,  but  is  simply  a  natural 
expression  of  the  reality  which  is  present.  It  is  Nature  we  are 
studying  in  biology,  not  a  special  "vital  force"  or  other  super- 
natural influence.  But  the  biologist  must  be  free  to  interpret 
Nature  in  his  own  way;  and  it  is  Nature  as  Hippocrates  saw  her, 
and  not  as  Democritus  saw  her,  that  he  sees  and  cannot  help 
seeing.  Organic  regulation,  maintenance,  and  reproduction  are 
nothing  but  the  expression  of  this  biological  Nature. 

The  universal  acceptance  among  biologists  of  the  doctrine  of 
evolution  has  often  been  assumed  to  carry  with  it  the  corollary  that 
life  has  arisen  out  of  inorganic  conditions ;  and  in  this  way  a  short 
cut  has  been  made  to  the  conclusion  that  biology  must  in  ultimate 
analysis  be  nothing  but  physics  and  chemistry.  This  reasoning 
cannot  be  justified.  Even  in  the  simplest  forms  of  life  it  is  still 
unmistakably  life  that  we  are  dealing  with ;  and  if  we  succeed  in 
tracing  life  to  yet  simpler  forms  we  shall  still  find  life,  so  that  the 
"inorganic  conditions"  into  which  we  have  traced  life  will  ap- 
pear to  be  something  very  different  from  inorganic  conditions 
as  we  now  represent  them  to  ourselves. 

We  can  see,  and  particularly  clearly  in  the  case  of  higher  or- 
ganisms, that  the  life  of  each  organism  is  an  association  of  the 
lives  of  more  elementary  organisms,  each  of  which  shows  its  full 
being  only  in  the  life  of  the  whole,  but  is  also  more  or  less  capable 
of  independent  existence.  It  is  by  the  separation  and  subsequent 
full  development  of  these  more  elementary  organisms  that  re- 
production is  brought  about.  The  life  of  a  higher  organism  has 
been  said  to  be  the  "sum"  of  the  lives  of  its  constituent  cells.  Such 
an  expression  is,  however,  misleading:  for  a  cell  apart  from  its 
particular  place  in  the  living  body,  or  the  particular  environment 
which  exists  there,  behaves  very  differently  from  the  same  cell 
in  its  proper  place.  It  thus  cannot  be  physiologically  defined  apart 
from  its  place  in  the  whole  organism.  The  organism  as  a  whole  is 
no  less  real  because  it  includes  in  its  life  the  lives  of  individual 
cells,  and  each  cell,  as  shown  very  clearly  in  connection  with  the 


RESPIRATION  397 

facts  first  discovered  by  Mendel  with  regard  to  reproduction,  in- 
cludes the  lives  of  still  more  elementary  centers  of  life.  The  same 
reasoning  applies,  of  course,  to  communities  of  what  appear  at 
first  to  be  quite  separate  organisms.  An  organism  separated  from 
its  kind  is  an  artificial  abstraction,  just  as  is  an  organism  separated 
in  other  ways  from  its  environment. 

Although  such  processes  as  respiration,  circulation,  secretion, 
absorption,  and  various  forms  of  nervous  activity,  occur  inde- 
pendently of  consciousness,  many  bodily  activities  are  accompa- 
nied by  consciousness.  Muscular  exertion,  for  instance,  is  for  the 
most  part  consciously  determined,  and  as  muscular  activity  de- 
termines breathing,  and  in  other  ways  the  breathing  is  determined 
by  conscious  activity  and  under  direct  conscious  control,  it  is 
necessary  to  refer  to  the  relation  of  conscious  to  unconscious 
bodily  activity. 

We  can  interpret  unconscious  physiological  activity  from  the 
biological  standpoint  which  has  hitherto  served  us  in  the  interpre- 
tation of  breathing,  circulation,  etc. ;  but  it  is  different  with  con- 
scious activity.  In  perception  we  are  aware  of  what  we  interpret 
as  "objective  reality/'  and  voluntary  actions  are  quite  evidently 
determined  by  this  awareness.  The  awareness  signifies  that  in 
perception,  as  distinguished  from  a  simple  physiological  reaction, 
the  reaction  is  not  simply  definable  as  occurring  at  a  certain 
moment  or  within  a  certain  definite  time,  but  involves  also  past 
and  future  times,  as  well  as  surrounding  space.  When  I  see  my 
pen  now,  I  see  it  as  a  material  structure  which  has  existed  and 
will  continue  to  exist.  I  also  see  it  as  being  in  relation  to  many 
other  things  not  at  the  moment  visible  in  the  physiological  sense. 
The  light  in  which  I  see  it  is  not  merely  that  of  an  electric  lamp 
but  of  all  my  other  experience.  When  I  write  with  the  pen  the 
movements  of  my  muscles  are  determined  by  the  actual  presence 
to  me  of  innumerable  past,  present,  and  anticipated  future  events 
in  both  my  own  individual  history  and  that  of  mankind.  The  past 
events  are  not  simply  past  and  done  with,  like  events  interpreted 
physically  or  biologically,  but  they,  and  not  their  mere  effects, 
are  still  present  and  active.  What  I  have  experienced  before,  what, 
for  instance,  I  have  read  of  Hippocrates,  or  Johannes  Muller,  or 
Claude  Bernard,  or  Paul  Bert,  is  still  taking  on  fresh  meanings  in 
my  mind  and  directly  determining  my  action  now.  The  same  is 
true  of  all  I  have  absorbed  of  the  common  spiritual  heritage  and 
anticipations  for  the  future  of  my  country  or  of  mankind.  Actual 
memory  is  no  mere  organic  memory.  I  am  living  and  acting  in  a 


398  RESPIRATION 

spiritual  world  for  which  separation,  not  merely  in  space,  but 
also  in  time,  has  none  of  the  meaning  which  it  possesses  for  the 
world  interpreted  physically  or  biologically.  Along  the  years 
and  across  the  oceans  action  and  reaction  are  direct  in  this  spirit- 
ual world. 

It  is  evident  that  in  conscious  activity  we  are  face  to  face  with 
facts  that  neither  physical  nor  biological  hypotheses  are  capable 
of  interpreting.  Yet  conscious  activity  manifests  itself  in  connec- 
tion with  the  same  beings  that  seem  also  to  live  and  breathe  as 
mere  organisms,  or  to  consist  of  nitrogen,  hydrogen,  oxygen, 
carbon,  and  other  atoms  leading  a  wild  and  undefinable  dance. 
In  presence  of  the  evidence  of  life  we  cannot  rest  satisfied  with  the 
physical  and  chemical  interpretation  of  these  beings ;  but  simi- 
larly in  the  presence  of  conscious  activity  we  cannot  rest  satisfied 
with  the  biological  interpretation.  Biological  phenomena  show 
us  that  the  physical  interpretation  of  the  universe  is  only  an  im- 
perfect preliminary  interpretation  for  which  all  that  can  be  said 
is  that  it  is  of  essential  practical  use  in  the  absence  of  fuller 
knowledge.  But  the  facts  relating  to  perception  and  volition  show 
us  that  the  biological  interpretation  is  also  no  more  than  a  prac- 
tical makeshift.  As  mathematicians,  physicists,  chemists,  biolo- 
gists, we  are  only  "practical"  men,  though  we  often  take  our 
practical  working  hypotheses  for  representations  of  actual  re- 
ality. We  do  so  by  unconsciously  neglecting  for  the  time  a  great 
part  of  the  facts  to  be  explained — in  particular  the  facts  that  our 
world  not  only  includes  living  organisms,  but  is  a  known  world 
and  a  world  of  spiritual  values.  In  reality  our  sciences  are  only 
making  use  of  abstractions  of  a  limited  practical  value.3 

In  conscious  activity  the  self-conserving  and  species-conserving 
organic  activities  of  living  organisms  take  on  a  new  and  far  wider 
interpretation.  Mere  organic  self-conservation  appears  now  as 
conservation  of  a  system  of  consciously  realized  interests;  and 
social  interests  assume  a  commanding  position  as  compared  with 
individual  interests.  In  so  far  as  bodily  interests  are  carried  out 
consciously,  therefore,  the  physiological  interpretation  of  them 
recedes  into  the  background ;  and  this  is  still  more  true  of  the 
physical  and  chemical  interpretation. 

In  the  preceding  chapters,  I  have  attempted  to  justify  the 
physiological  interpretation  of  unconscious  bodily  activities  by 
pointing  out  how  breathing,  circulation,  etc.,  are  manifestations 

3  A  fuller  discussion  of  this  point  of  view  will  be  found  in  my  book  "Mech- 
anism, Life  and  Personality,"  New  Edition,  1921. 


RESPIRATION  399 

of  the  maintenance  of  organic  identity.  Up  to  a  certain  point  one 
can  apply  the  same  reasoning  to  conscious  activities  by  showing 
how  exquisitely  dependent  they  are  from  moment  to  moment  on 
the  integrity  of  normal  "conditions  of  life"  in  the  internal  en- 
vironment, and  how  they  play  their  part  in  maintaining  this  in- 
tegrity in  accordance  with  Claude  Bernard's  conception.  But  such 
treatment  of  them  is  wholly  insufficient,  since  they  evidently  par- 
ticipate in  that  spiritual  world  to  which  reference  has  already 
been  made.  Hence  they  cannot  be  described  in  terms  of  the  work- 
ing hypotheses  of  biology,  and  attempts  to  describe  them  ade- 
quately in  such  terms  are  merely  childish.  A  fortiori  they  cannot 
be  described  in  physical  terms. 

Perception  and  volition  are  often  referred  to  as  processes  occur- 
ring in  the  cerebral  hemispheres  as  a  result  of  physical  impulses 
communicated  along  sensory  nerves  from  outside.  For  certain 
limited  practical  purposes  this  is  a  useful  view  to  take  of  them. 
But,  as  already  pointed  out,  perception  and  volition  as  such  are 
not  capable  of  description  as  events  occurring  at  a  certain  time  and 
place,  since  from  their  very  nature  they  include  other  times  and 
places,  and  may  be  said  to  be  creative  of  time  and  space.  The 
working  conception  under  which  we  attempt  to  describe  them  as 
events  occurring  here  and  now  is  totally  inadequate;  and  in  so 
far  as  we  express  them  in  terms  of  this  conception  we  reduce  them 
to  mere  abstractions.  By  a  process  of  abstraction  we  can  observe 
in  ourselves  and  interpret  as  mere  physiological  or  even  physical 
events  our  perceptions  and  voluntary  actions.  These  observations 
constitute  an  important  part  of  our  existing  practical  knowledge, 
but  they  belong  to  physics  or  physiology,  and  not  to  psychology, 
since  in  making  them  we  deliberately  leave  out  of  account  all  that 
is  characteristic  of  conscious  activity. 

To  those  who  argue  that  all  our  conscious  activities  are  depend- 
ent on  physical  conditions,  the  reply  is  that  "physical  conditions" 
are  in  ultimate  analysis  only  imperfect  abstractions.  If  once  we  re- 
gard them  as  anything  more,  we  are  plunged  into  all  the  difficul- 
ties which  modern  philosophy  since  Descartes  has  been  continu- 
ously and  successfully  grappling  with.  The  universe  is  a  spiritual 
universe,  and  not  a  dualistic  universe  of  matter  and  mind. 

This  book  is  concerned  with  physiology  and  not  psychology. 
I  have  claimed  for  physiology  its  rightful  practical  sphere  in 
distinction  from  that  of  physics  and  chemistry.  But  we  have 
reached  a  limit  to  the  sphere  of  physiology  when  we  come  to  deal 
with  conscious  activity. 


APPENDIX 

THIS  appendix  contains  a  description  and  discussion  of  several  special 
methods  of  blood  examination  associated  with  my  name,  together  with 
modifications  introduced  by  myself  and  others  since  the  methods  were 
originally  described.  Methods  of  gas  analysis  are  not  included,  since 
these  are  collected  in  my  book  "Methods  of  Air  -Analysis." 

Until  a  few  years  ago  the  gases  present  in  the  easily  dissociable  and 
free  state  in  blood  were  universally  determined  by  means  of  the  mercurial 
vacuum  pump,  which  had  been  gradually  perfected  by  Lothar  Meyer, 
Ludwig,  Pfliiger,  and  others,  while  Leonard  Hill  had  considerably 
simplified  it  for  ordinary  uses.  It  required,  however,  an  inconveniently 
large  amount  of  blood  and  was  also  not  very  accurate,  since  even  when 
large  volumes  of  blood  were  used  errors  due  to  gas  adhering  to  the  glass 
could  not  be  avoided.  The  presence  of  these  errors  was  clearly  shown  by 
the  fact  that  the  amount  of  nitrogen  apparently  obtained  from  the  blood 
was  not  only  variable,  but  much  greater  than  the  amount  which  the  blood 
was  capable  of  dissolving.  The  excess  of  nitrogen  could  be  calculated  as 
due  to  contamination  with  air  from  the  pump;  but  this  correction  was 
not  very  satisfactory,  since  gas  must  also  be  left  in  the  pump  at  the  end 
of  the  operation  of  pumping.  The  discovery  which  I  made  in  1897,  that 
oxygen  or  CO  can  be  liberated  quantitatively  from  oxyhaemoglobin  or 
CO -haemoglobin  by  ferricyanide,1  made  it  possible  to  dispense  with  the 
blood  pump  and  greatly  simplify  blood-gas  determination  and  increase 
its  accuracy.  With  the  new  method  Lorrain  Smith  and  I  found  also  that 
the  oxygen  capacity  of  blood  varies  exactly  as  its  coloring  power,  so  that 
the  oxygen  capacity  can  be  determined  colorimetrically.  The  methods 
now  to  be  described  are  based  partly  on  the  ferricyanide  reaction  and 
partly  on  the  colorimetry  of  blood. 

A.  Determination  of  Oxygen  Capacity  of  Blood  Haemoglobin 

by  Ferricyanide 

The  following  method  of  determining  very  accurately  the  oxygen 
capacity  of  the  haemoglobin  in  blood  or  a  solution  of  haemoglobin  was 
first  fully  described  in  ipoo.2  Although  the  oxygen  capacity  can  be  de- 
termined with  much  smaller  quantities  of  blood  by  the  apparatus  de- 
scribed below,  it  seems  useful  to  describe  also  the  earlier  method,  as  it 

^aldane,  Journ.  of  Physiol.,  XXII,  p.  298,  1898. 
2  Haldane,  Journ.  of  Physwl.,  XXV,  p.  295,  1900. 


RESPIRATION 


401 


can  be  carried  out  with  very  simple  apparatus,  easily  put  together  in  any 
laboratory,  and  suitable  not  only  for  exact  research,  but  for  use  by 
students.  The  chemical  facts  on  which  the  method  is  based  have  already 
been  referred  to  in  Chapter  IV. 

The  apparatus  is  shown  in  Figure  101  and  the  process  is  as  follows. 
Twenty  cc.  of  the  oxalated  or  defibrinated  blood  thoroughly  saturated 
with  air  by  rotating  it  in  a  large  flask,  are  measured  out  from  a  pipette 
into  the  bottle  A,  which  has  a  capacity  of  about  120  cc. 


Figure  101. 

Apparatus  for  determining  the  oxygen  capacity  of  haemo- 
globin in  blood. 

As  it  is  important  to  avoid  blowing  expired  air  into  the  bottle,  the 
last  drops  of  blood  are  expelled  from  the  pipette  by  closing  the  top  and 
warming  the  bulb  with  the  hand.  In  filling  the  pipette,  care  must  also  be 
taken  that  the  corpuscles  have  not  had  time  to  begin  to  subside  in  the 
vessel  from  which  the  pipette  is  filled.  Thirty  cc.  are  then  added  of  a 
solution  prepared  by  diluting  ordinary  strong  ammonia  solution,  (sp. 


402  RESPIRATION 

gr.  0.88)  with  distilled  water  to  i/25oth,  and  the  mixture  shaken.  The 
ammonia  solution  prevents  CO2  from  coming  off  and  also  lakes  the 
blood.  Unless  the  blood  is  laked,  the  ferricyanide  cannot  act  on  the 
haemoglobin,  since  the  corpuscle  walls  are  impermeable  to  ferricyanide. 
About  4  cc.  of  a  saturated  solution  of  potassium  ferricyanide  are  then 
poured  into  the  small  tube  B  (the  length  of  which  should  slightly  exceed 
the  size  of  the  bottle)  and  placed  upright  in  A.  The  rubber  stopper,  which 
is  provided,  as  shown,  with  a  bent  glass  tube  connected  with  the  burette 
by  stout  rubber  tubing  of  about  i  mm.  bore,  is  then  firmly  inserted, 
and  the  bottle  placed  in  the  vessel  of  water  C,  the  temperature  of 
which  should  be  as  nearly  as  possible  that  of  the  room  and  of  the 
liquid  in  the  bottle.  If  the  stopper  is  not  heavy  enough  to  sink  the  bottle, 
the  latter  should  be  weighted.  By  opening  to  the  outside  the  three-way 
tap  (or  a  T  tube  and  clip)  on  the  burette,  and  raising  the  leveling  tube, 
which  is  held  by  a  spring  clamp,  the  water  in  the  burette  is  brought  to 
a  level  close  to  the  top.  The  tap  or  T  tube  is  then  closed  to  the  outside, 
and  the  reading  of  the  burette  (which  should  be  graduated  to  .05  cc.,  and 
read  to  .01  cc.)  taken  after  careful  leveling,  as  soon  as  the  temperature 
has  become  constant,  as  shown  by  the  constancy  of  the  reading.  Mean- 
while the  water  gauge  (which  has  a  bore  of  about  2  mm.)  attached  to  the 
temperature  and  pressure-control  tube  is  accurately  adjusted  to  a  defi- 
nite mark.  This  is  easily  accomplished  by  sliding  the  rubber  backwards 
or  forwards  on  the  narrow  glass  tube  D.  The  control  tube  is  an  ordinary 
test  tube  containing  some  mercury  to  sink  it. 

As  soon  as  the  reading  of  the  burette  is  constant,  the  bottle  is  tilted  so 
as  to  upset  B,  and  is  shaken  as  long  as  the  gas  is  evolved.  During  this 
operation  B  should  be  repeatedly  emptied,  as  otherwise  the  oxygen  dis- 
solved in  its  liquid  might  not  be  completely  given  off.  When  the  evolution 
of  gas  has  ceased,  the  bottle  is  replaced  in  the  water.  If,  as  is  probable, 
the  very  sensitive  pressure  gauge  indicates  an  alteration  in  the  tempera- 
ture of  the  water,  cold  water  from  a  tap,  or  else  warmed  water,  is  added 
till  the  original  temperature  has  been  reestablished,  and  the  reading  of 
the  burette  noted  as  soon  as  it  is  constant.  The  bottle  is  again  shaken, 
etc.,  to  make  sure  that  the  result  is  constant;  and  usually  about  fifteen 
minutes  will  be  needed  to  complete  the  operations.  The  temperature  of 
the  water  in  the  jacket  of  the  burette3  and  the  reading  of  the  barometer 
are  now  taken,  and  the  oxygen  evolved  is  reduced  to  its  dry  volume  at  o° 
and  760  mm.  A  table  can  be  used  for  the  reduction,  and  one  is  given  in 
Methods  of  Air  Analysis. 

*  The  jacketing  of  the  burette  may  be  omitted,  in  which  case  the  thermometer 
should  be  suspended  with  its  bulb  close  to  the  upper  part  of  the  burette. 


RESPIRATION  403 

To  calculate  the  oxygen  evolved  from  100  cc.  of  blood,  allowance  must 
be  made  for  the  fact  that  a  20  cc.  pipette  does  not  deliver  20  cc.  of  blood, 
but  only  about  19.6  cc.  The  actual  amount  of  shortage  can  easily  be 
determined  by  weighing.  A  further  slight  correction  is  needed  on  ac- 
count of  the  fact  that  the  air  in  the  bottle  at  the  end  of  the  operation  is 
richer  in  oxygen  than  at  the  beginning,  so  that,  as  oxygen  is  about  a 
third  more  soluble  than  air,  slightly  more  gas  will  be  in  solution.  With  a 
bottle  of  120  cc.  capacity  and  20  per  cent  of  oxygen  in  the  blood,  the  air 
in  the  bottle  will  evidently  contain  about  26  per  cent  of  oxygen,  so  that, 
assuming  that  the  coefficients  of  absorption  of  oxygen  and  nitrogen  in 
the  54  cc.  of  liquid  in  the  bottle  are  nearly  the  same  as  in  water,  the 
correction  will  amount  at  15°  to  .03  cc.  in  the  reading  of  the  burette,  if 
the  oxygen  capacity  is  normal,  or  0.75  per  cent  of  the  oxygen  given  off. 

In  order  to  make  quite  sure  that  no  oxyhaemoglobin  remains  in  the 
solution  owing  to  a  reshrinkage  of  corpuscles  on  adding  the  ferricyanide, 
and  consequent  escape  of  some  of  the  oxyhaemoglobin  from  the  action 
of  the  ferricyanide,  the  liquid  in  the  bottle  can  afterwards  be  examined 
as  follows.  Part  of  it  is  diluted  with  0.8  per  cent  salt  solution,  shaken  up 
in  a  test  tube  with  expired  air  so  as  to  render  the  solution  just  acid,  and 
examined  spectroscopically.  Any  trace  of  oxyhaemoglobin  left  in  incom- 
pletely laked  corpuscles  is  shown  by  the  presence  of  the  characteristic 
absorption  bands.  These  are  completely  absent  if  only  methaemoglobin 
is  present,  as  ought  to  be  the  case.  If  they  are  present  the  result  will  be 
too  low,  and  the  experiment  must  be  repeated  with  saponin  added. 

If  the  blood  is  saturated  with  CO  instead  of  oxygen  the  reaction  is 
slower,  but  gives  precisely  the  same  result.  The  correction  for  physically 
dissolved  gas  is,  however,  scarcely  appreciable,  as  CO  is  very  little  more 
soluble  than  air.  If  the  blood  has  begun  to  decompose,  owing  to  bacterial 
action,  the  result  will  of  course  be  too  low,  and  this  can  easily  be  detected, 
because  of  the  fact  that  each  successive  reading  of  the  burette  will  be 
lower,  owing  to  the  disappearance  of  oxygen.4  There  is  no  appreciable 
error,  owing  to  the  tension  of  ammonia  vapor  in  the  air ;  and  the  method 
is  one  of  extreme  accuracy  and  certainty.  Different  determinations  ought 
not  to  differ  by  more  than  i/2ooth  of  the  quantity  measured.  On  com- 
paring the  results  with  those  from  the  pump,  after  allowance  in  the  case 
of  the  pump  for  oxygen  in  simple  solution  in  the  blood,  or  adhering  to 

4  Under  certain  abnormal  conditions  even  fresh  mammalian  blood,  as  Douglas 
(Journ.  of  PAysiol.,  p.  453,  1910)  has  shown,  may  in  presence  of  the  ferricyanide 
absorb  an  appreciable  amount  of  oxygen  before  a  determination  is  complete :  in 
which  case  the  quicker  method  described  below  is  greatly  preferable.  An  appreciable 
absorption  can  also  be  detected  in  normal  fresh  human  blood  left  for  an  hour  or 
two  in  the  apparatus. 


404  RESPIRATION 

the  glass  in  the  pump,  I  obtained  the  following  results,  using  a  large- 
sized  Bohr  pump  with  every  precaution. 


VOLUMES  OF  OXYGEN  PER 

ioo  VOLUMES  OF  BLOOD 

By  blood            By  ferricyanide 
•pump                       method 

Defibrinated  ox  blood 

24.38 

24.43 

i 

24-35 

Oxalated 

20.36 

20.47 

20.57 

22.2O 

Oxalated 

22.40 

Average 

22.33 

22.38                         22.39 

B.  Determination  of  Oxygen  Capacity  of  Blood  Haemoglobin 
by  Haemoglobinometer 

Colorimetric  methods  of  estimating  the  relative  concentrations  of 
haemoglobin  in  blood  have  been  used  for  long;  and  in  1878  the  late 
Sir  William  Gowers  introduced  his  well-known  and  extremely  con- 
venient "haemoglobinometer"  for  clinical  purposes.5  In  this  apparatus 
there  are  two  tubes  A  and  B  (Figure  102)  of  equal  diameter;  A  is 
sealed  and  contains  picrocarmine  jelly  of  such  strength  and  composition 
that  when  20  cubic  millimeters  of  normal  human  blood  are  diluted  with 
water  in  the  tube  B  to  the  mark  ioo,  the  tints  of  the  liquid  in  the  two 
tubes  are  the  same.  If  the  blood  contains  abnormally  little  or  much 
haemoglobin,  the  quantity  of  water  required  to  produce  the  tint  of  the 
standard  picrocarmine  solution  will  be  correspondingly  less  or  more, 
so  that  the  percentage  of  the  normal  proportion  of  haemoglobin  can  be 
read  off  on  the  tube.  The  diameter  of  the  tubes  and  strength  of  the 
picrocarmine  or  haemoglobin  solution  are  so  chosen  that  any  variation 
from  the  normal  strength  can  be  perceived  with  the  maximum  of  readi- 
ness. A  solution  much  stronger  or  weaker  would  not  be  suitable.  The 
design  is  thus  not  only  extremely  convenient,  but  also  thoroughly  cor- 
rect in  principle. 

When  it  was  discovered  that  the  coloring  power  and  oxygen  capacity 
of  haemoglobin  are  strictly  proportional  to  one  another  it  became  evident 

5  Gowers,  Trans.  Clinical  Soc.,  XII,  p.  64,  1878. 


RESPIRATION 


405 


that  the  Gowers  haemoglobinometer  could  be  made  a  very  exact  instru- 
ment for  determining  the  oxygen  capacity  of  blood,  and  could  also  be 
improved  in  other  respects.  I  introduced  the  necessary  improvements  in 
1 90 1.6  For  the  picrocarmine  solution  there  is  substituted  a  i  per  cent 
solution  of  blood  with  an  oxygen  capacity  of  18.5  cc.  per  100  cc.  of  blood, 
since  the  average  of  a  number  of  normal  men  showed  that  this  is  the 
average  oxygen  capacity  for  men.  To  make  this  solution  keep  its  coloring 


Figure  102. 

Gowers-Haldane  Haemoglobinometer 

A — Glass  tube  containing  blood  solution  of  standard  tint. 
B — Graduated  tube. 
C — Rubber  stand  for  tubes  A  and  B. 
D — Capillary  pipette  and  suction  tube ;  wires  for  cleaning 

the  pipette  are  supplied. 
E — Bottle  with  pipette  stopper. 
F — Glass  tube  holding  6  lancets. 
G — Tube  and  cap  for  fixing  over  ordinary  gas  burners. 

power  it  is  saturated  with  CO,  and  sealed  up  with  only  CO,  and  no  oxy- 
gen, in  the  empty  space  above  the  blood  solution.  Hoppe  Seyler  had 
already  found  that  a  strong  solution  of  CO-haemoglobin  retains  its 
coloring  power.  This  is  also  true  for  a  dilute  solution ;  and  the  standard 
haemoglobinometer  tubes  filled  and  sealed  twenty  years  ago  have  re- 
mained absolutely  unaltered  in  color. 

*  Haldane,  Journ.  of  Physwl.,  XXVI,  p.  497,   1901.  The  instrument  is  made 
by  Hawksley,  Wigmore  Street,  London,  W. 


406  RESPIRATION 

One  defect  of  the  picrocarmine  tubes  arose  from  the  fact  that  the  picro- 
carmine  is  not  completely  stable,  so  that  after  a  time  its  color  alters.  But 
even  the  original  standard  was  somewhat  indefinite,  depending  as  it 
did  on  the  particular  percentage  of  haemoglobin  in  the  sample  of  normal 
blood  with  which  it  was  standardized.  Another  defect  depended  on  the 
fact  that  the  colors  of  the  blood  and  picrocarmine  solution  are  not  the 
same  spectrally.  In  consequence  of  this  a  color  match  with  one  quality 
of  light  is  no  longer  a  match  with  a  different  quality  of  light.  Thus  in 
ordinary  artificial  light  the  reading  of  the  instrument  is  quite  different 
from  that  in  average  daylight ;  and  in  different  qualities  of  daylight,  and 
with  different  observers,  the  match  differs.  The  same  defect  exists  in 
various  later  forms  of  haemoglobinometer,  where  colored  glass  or  colored 
paper  is  used  as  a  standard.  By  using  CO  haemoglobin  as  the  standard 
solution,  and  saturating  the  blood  under  examination  with  CO  or  coal 
gas  these  defects  are  avoided. 

To  avoid  errors  due  to  inequality  in  the  diameters  of  the  tubes,  each 
tube  has  first  of  all  two  marks  placed  on  it — the  first  at  the  level  when 
.2  cc.  of  water  are  introduced  into  a  dry  tube,  and  the  second  at  the 
level  given  by  2  cc.  The  distance  between  these  two  marks  must  corre- 
spond exactly  in  the  standard  tube  and  measuring  tube  and  this  must  be 
borne  in  mind  if  either  tube  gets  broken  and  has  to  be  replaced.  The 
20  cubic  millimeter  pipette  is  also  standardized  by  weighing  on  a  deli- 
cate balance. 

To  make  a  determination,  some  water  is  first  introduced  into  the 
measuring  tube.  Twenty  cmm.  of  blood  from  a  prick  in  the  finger  or 
ear  are  then  measured  into  this  water  from  the  dry  pipette.  The  blood 
sinks,  and  the  pipette  is  rinsed  out  with  some  of  the  water  standing  above 
the  blood.  Some  coal  gas  or  CO  is  then  run  into  the  upper  part  of  the 
measuring  tube  through  narrow  rubber  or  glass  tubing,  and  the  top  of 
the  tube  promptly  closed  with  the  finger.  With  the  thumb  of  the  same 
hand  on  the  lower  end  of  the  tube  the  latter  is  then  inverted  several 
times  so  as  to  saturate  the  haemoglobin  completely  with  CO,  but  without 
warming  the  contents  of  the  tube.  The  finger  can  then  be  slid  off  the 
open  end  of  the  tube  without  the  slightest  loss  of  liquid.  More  water 
is  now  added  by  means  of  the  dropping  pipette  until  the  tints  appear 
equal.  When  this  point  is  reached  the  level  is  read  off  after  a  short  inter- 
val to  allow  liquid  to  run  down.  Another  drop  is  introduced,  and  then 
another,  until  the  tints  appear  unequal  again;  and  the  mean  of  the 
readings  giving  equality  is  taken  as  showing  the  required  percentage. 
This  indicates  the  oxygen  capacity  of  the  haemoglobin  in  percentages  of 
18.5  cc.  of  oxygen  capacity  per  100  cc.  of  blood. 

In  judging  of  equality  in  tint  the  tubes  are  held  up  before  a  window 


RESPIRATION  407 

or  an  opal  shade  covering  a  gas  flame  or  electric  lamp.  At  every  observa- 
tion the  tubes  are  transposed.  This  is  essential  since  it  will  be  found 
that  in  all  probability  the  tint  of  one  tube  will  appear  deeper  when  it  is 
held  on  one  side  than  when  on  the  opposite  side.  If,  for  instance,  the 
tubes  are  nearly  equal  in  depth  of  color  they  will  appear  equal  when  one 
tube  is  on  the  right  or  left  side,  but  not  vice  versa.  A  slight  inequality 
of  this  kind  is  rather  a  help  to  accuracy,  as  probably  only  one  reading 
will  give  equality  on  both  sides.  With  careful  work  any  error  in  a  de- 
termination should  not  exceed  0.5  per  cent.  The  method  is  thus  one  of 
great  accuracy. 

It  is  often  loosely  assumed  that  colorimetric  estimations  are  uncertain. 
This  is  certainly  not  the  case  if  they  are  properly  carried  out,  with  ap- 
preciation of  the  precautions  needed  to  avoid  the  errors  referred  to 
above,  of  physiological  origin.  Another  common  misconception  is  that  a 
uniform  colored  surface  is  necessary,  and  that,  as  a  tube  does  not  give 
this,  a  method  such  as  that  just  described  must  be  inaccurate.  The 
surfaces  need  not  be  uniform,  provided  they  are  similar  to  one  another, 
as  in  the  case  of  two  similar  tubes. 

The  correctness  of  a  Gowers-Haldane  haemoglobinometer  can  be 
checked  at  any  time  by  the  ferricyanide  method  described  under  A  or 
C.  Another  check  on  the  correctness  of  the  standard  solution  is  that  it 
must  have  practically  the  same  pink  tint  as  fresh  blood  saturated  with 
CO.  If  there  has  been  any  defect  in  filling,  the  standard  tube  will  appear 
yellower.  With  a  proper  standard  tube  one  can  tell  at  once  by  the 
absence  or  presence  of  yellow  color  whether  a  patient's  blood  is  free  from 
methaemoglobin  or  other  abnormal  blood  pigments. 

For  ordinary  clinical  work  it  is  convenient  to  work  ordinarily  with  a 
picrocarmine  standard  tube,  and  only  occasionally  ascertain  the  correc- 
tion necessary  with  this  standard.  The  correction  can  easily  be  made  by 
comparing  the  results  for  the  same  person  and  time  with  the  two  tubes. 

C.  Determination  of  Oxygen  and  Carbon  Dioxide  in  Blood  by 
Ferricyanide  and  Acid 

As  mentioned  in  Chapter  IV,  a  method,  based  on  the  use  of  ferri- 
cyanide, was  described  in  a  paper  by  Mr.  Barcroft  and  myself  in  I9O2.7 
The  principle  of  this  method  is  that,  without  permitting  any  previous 
contact  of  the  blood  with  air,  the  oxygen  of  a  small  measured  volume  of 
blood  is  liberated  by  ferricyanide  in  a  closed  vessel,  and  the  pressure 
produced  by  the  liberation  measured  without  any  alteration  being  allowed 
in  the  volume  of  gas  in  the  vessel.  The  CO2  is  then  similarly  liberated  by 

7  Barcroft  and  Haldane,  Journ.  of  Physiol.,  XXVIII,  p.  232,  1902. 


408  RESPIRATION 

acid,  and  its  pressure  measured.  When  certain  corrections  are  made,  it 
is  then  possible  to  estimate  either  the  total  oxygen  and  total  CO2,  or  the 
combined  oxygen  and  combined  CO2  in  the  blood.  The  gas  is  measured 
by  the  increase  of  pressure  at  constant  volume,  and  not  by  the  increase 
of  volume  at  constant  pressure.  Theoretically,  either  method  is  correct, 
in  accordance  with  Boyle's  Law ;  but  as  Barcroft  required  a  method  for 
dealing  with  very  small  quantities  of  blood,  and  a  very  delicate  pressure- 
gauge  was  needed  in  any  case,  it  seemed  simpler  to  graduate  the  pres- 
sure gauge  in  millimeters,  and  keep  the  gas  at  constant  volume,  retain- 
ing, however,  the  control  vessel,  as  in  the  original  form  of  apparatus. 
I  therefore  designed  the  apparatus  as  it  was  originally  figured  in  our 
paper,  and  the  tests  we  made  gave  very  satisfactory  results  so  far  as 
they  went. 

One  defect  of  the  apparatus  described  in  the  previous  section  is  that 
a  considerable  time  is  needed  to  reach  temperature  equilibrium  and  to 
shake  out  all  the  extra  free  oxygen  from  the  blood  solution.  The  latter 
defect  would  apply  still  more  to  an  apparatus  in  which  CO2  had  to  be 
shaken  out.  In  the  new  apparatus  the  volume  of  liquid  was  therefore 
greatly  diminished,  and  the  relative  volume  of  air  to  blood  solution 
greatly  increased;  and  this  was  also  rendered  advisable  owing  to  the 
fact  that  nearly  as  much  CO2  remains  in  solution  in  the  liquid  as  is 
present  in  an  equal  volume  of  air.  The  increased  volume  of  air  had, 
however,  the  disadvantages,  first  that  the  pressure  of  ammonia  in  the 
air  introduced  an  appreciable  source  of  error,  and  secondly  that  much 
more  care  was  needed  as  to  temperature  equilibrium  in  the  blood  vessel 
and  control  vessel.  A  further  source  of  error  was  slight  variation  in 
capillarity  at  different  levels  in  the  gauges  of  the  blood  vessel  and 
control  vessel.  In  spite  of  all  improvements  in  this  apparatus  and  the 
methods  of  using  it,  there  appears  to  be  a  range  of  error  with  it  of  at 
least  2  per  cent  of  the  quantity  measured,  even  when  the  error  due  to 
ammonia  vapor  is  completely  eliminated. 

The  apparatus  was  rendered  much  more  convenient,  though  also  less 
easy  to  make  or  repair,  by  Brodie.8  It  was  also  simplified  by  Barcroft; 
who  named  his  modification  the  "differential"  apparatus.9  Barcroft  con- 
nects the  gauges  of  the  blood  vessel  and  control  vessel,  so  that  there  is 
only  one  manometer  instead  of  two,  and  estimates  the  gas  given  off  from 
the  readings  of  this  compound  gauge.  With  this  construction  the  ap- 
paratus works  at  neither  constant  volume  nor  constant  pressure,  so  that 
the  gas  given  off  cannot  be  correctly  deduced  from  the  mere  readings  of 
the  gauges.  He  therefore  calibrates  the  apparatus  empirically  with  the 

8  Brodie,  Journ.  of  Physiol.,  XXXIX,  p.  391,  1910. 

9  Described  fully  in  Barcroft's  book,  The  Respiratory  Functions  of  the  Blood. 


RESPIRATION  409 

help  of  the  oxygen  liberated  from  a  titrated  solution  of  hydrogen  perox- 
ide. But  this  is  a  rather  serious  complication,  and  even  if  the  calibration  is 
correctly  made  it  can  only  apply  correctly  at  a  certain  barometric  pressure 
and  would  not  be  quite  valid  over  the  variations  of  barometric  pressure 
ordinarily  met  with.  I  cannot,  therefore,  regard  this  plan  as  satisfactory 
for  some  kinds  of  exact  work.  On  the  other  hand  this  objection 
does  not  apply  where  the  empirical  calibration  is  not  needed,  as  in 
determinations  of  the  percentage  saturation  of  haemoglobin  with  oxy- 
gen— for  instance  in  investigating  dissociation  curves  of  oxyhaemo- 
globin.  Barcroft  has  also  devised  a  small  model,  for  which  only  o.i  cc. 
of  blood  is  required. 

A  very  different  form  of  the  ferricyanide  method  has  recently  been 
introduced  by  Yandell  Henderson  and  Smith.10  The  blood  (i  cc.)  is 
introduced  (under  ammonia  solution  without  contact  with  air,  just  as 
in  the  Barcroft-Haldane  method)  into  the  bottom  of  a  diffusion  tube 
of  about  12  cc.  capacity.  This  tube  is  provided  with  a  3-way  tap  at  the 
bottom  end  and  a  thin  rubber  stopper  at  the  top,  and  is  graduated  for  a 
short  distance  from  the  top.  A  fine  hypodermic  needle  is  then  thrust 
through  the  rubber  to  equalize  the  pressure  inside  and  outside  of  the 
tube,  the  needle  withdrawn,  and  the  blood  and  ammonia  solution  mixed 
so  as  to  lake  the  blood.  Ferricyanide  solution  is  then  injected  through  the 
stopper,  and  the  tube  rotated  for  five  minutes  so  that  the  whole  excess 
of  free  oxygen  diffuses  out  into  the  air  of  the  tube.  The  tube  is  then 
inverted  and  the  stopper  removed  under  water  so  that  the  pressure  inside 
and  outside  the  tube  is  equalized.  The  volume  of  gas  in  the  tube  is  read 
off ;  and  finally  nearly  the  whole  of  this  gas  is  drawn  into  a  Haldane  gas- 
analysis  apparatus,  and  the  oxygen  percentage  determined.  From  the 
increased  oxygen  percentage  of  this  gas  as  compared  with  air,  and  the 
volume  of  gas  in  the  tube,  the  oxygen  given  off  by  the  blood  can  easily 
be  calculated.  The  CO2  in  the  blood  is  estimated  similarly;  and  both 
oxygen  and  CO2  can  be  estimated  in  the  same  sample  of  blood.  This 
method  seems  to  be  about  as  accurate  as  the  Barcroft-Haldane  method, 
and  to  be  easier  for  those  familiar  with  accurate  gas  analysis.  It  appears 
to  be  specially  suitable  for  comparisons  of  the  arterial  and  venous  blood 
in  animals ;  and  evidently  any  CO  in  blood  can  be  estimated  conveniently 
by  this  method,  which  also  has  the  advantage  that  corrections  for  physical 
solution  of  gases  are  greatly  reduced. 

Still  another  method  is  to  use  the  Van  Slyke  vacuum  apparatus  in 
connection  with  ferricyanide.11  This,  however,  involves  the  various 

10  Yandell  Henderson  and  Smith,  Journ.  of  Bwl.  Chem.,  XXXIII,  p.  39,   1918. 

11  Van  Slyke,  Journ.  of  Bwl.  Chem.,  XXX,  p.  347,  1917  ;  and  XXXIII,  p.  127, 
1918 


4io  RESPIRATION 

sources  of  error  connected  with  the  use  of  a  vacuum  pump,  or  necessitates 
analysis  of  the  gas  obtained  from  the  blood. 

Until  recently  we  have  used  at  Oxford  the  Brodie  modification  of  the 
Barcroft-Haldane  apparatus.  As,  however,  the  range  of  error  with  this 
apparatus  has  been  about  2  per  cent,  I  have  quite  recently  devised  a 
new  apparatus,  with  a  view  especially  to  more  accurate  determinations 
of  the  oxygen  in  human  arterial  blood,  and  of  dissociation  curves.12 
With  this  apparatus  it  is  possible  to  reach  an  accuracy  as  great  as  with 
the  original  ferricyanide  apparatus — i.e.,  to  within  0.5  per  cent  of  the 
oxygen  capacity  of  the  blood.  This  new  apparatus  will  therefore  be  de- 
scribed in  full.  On  account  of  the  present  difficulty  and  expense  in  getting 
glass  apparatus  made,  it  was  designed  so  that  it  could  if  necessary  be 
put  together  in  a  laboratory  from  easily  obtainable  parts,  just  as  in  the 
case  of  the  original  apparatus. 

When  blood  from  a  blood  vessel  is  used,  a  glass  syringe  with  solid 
glass  piston  is  employed  for  obtaining  the  sample.  This  method  was  first 
applied  to  human  arteries  by  Hiirter,  and  developed  by  Stadie  and  others. 
Professor  Meakins,  with  whom  I  have  been  associated  in  work  on  human 
blood  gases,  employs  the  following  procedure.  A  very  small  quantity  of 
finely  powdered  potassium  oxalate  is  introduced  into  the  bottom  of  the 
syringe.  The  piston  is  then  introduced  and  a  little  liquid  paraffin  drawn 
in,  and  as  much  as  possible  expelled  again  with  the  syringe  pointing 
upwards  so  as  not  to  expel  the  oxalate.  After  disinfection  of  the  skin  the 
needle  (previously  sterilized)  is  introduced  into  the  radial  artery  or  other 
vessel,  and  about  5  cc.  or  more  of  blood  withdrawn,  a  compress  and 
bandage  being  afterwards  applied  over  the  place  for  an  hour  if  the 
vessel  was  an  artery.  The  needle  is  then  removed  and  washed,  and  the 
blood  transferred  (with  the  syringe  pointing  upwards)  through  a  rubber 
connection  into  a  graduated  pipette  holding  more  than  2  cc.  From  this 
pipette  an  exactly  measured  quantity  of  about  2  cc.  is  introduced  beneath 
the  sodium  carbonate  or  ammonia  solution  in  the  blood-gas  flask.  At  the 
end  of  the  operation  about  0.5  cc.  remains  in  the  pipette,  so  that  none 
of  the  blood  has  come  in  contact  with  air. 

The  apparatus  is  shown  in  Figure  103.  In  principle  it  is  similar  to  that 
shown  in  Figure  101,  but  designed  for  small  quantities  of  blood  and  for 
determining  CO2.  The  blood  is  received  in  one  of  the  small  flasks  shown, 
while  the  other  is  for  temperature  control.  Each  has  a  capacity  of  about 
20  cc.  The  procedure  differs  according  as  it  is  desired  to  determine  the 
oxygen  or  the  CO2  of  the  blood.  In  the  former  case  the  first  step  is  to 
measure  2  cc.  of  a  i  per  cent  solution  of  dried  sodium  carbonate  into 
one  of  the  two  small  flasks  (about  20  cc.  capacity)  shown  and  add  a 

"Haldane,  Journ.  of  Pathol.  and.  Bacterial.,  XXIII,  p.  443,  1920. 


RESPIRATION 


411 


small  quantity  of  saponin  on  the  point  of  a  penknife.  Exactly  2  cc.,  or  at 
any  rate  an  exactly  determined  volume,  of  the  blood  is  then  measured 
out  from  the  pipette  into  the  flask  beneath  the  sodium  carbonate  solution. 
The  flask  is  then  firmly  corked  and  completely  immersed  beyond  the 
cork  in  the  bath  alongside  the  other  (control)  flask  until  the  temperature 


Figure  103. 
Apparatus  for  blood-gas  analysis. 

of  the  air  in  the  flask  becomes  completely  steady.  The  flasks  are  con- 
nected, as  shown,  by  means  of  thick-walled  rubber  tubing  of  about  2  mm. 
bore  with  the  two  gauges  and  gas  burette  fixed  on  the  wooden  stand.  The 
glass  connections,  taps,  and  gauges  are  also  of  2  mm.  bore,  and  so  ar- 
ranged that  the  connections  of  the  two  flasks  are  of  equal  volume.  The 
burette  itself  consists  of  an  ordinary  i  cc.  dropping  pipette  divided  to 
.01  cc.,  and  therefore  capable  of  being  read  to  .002  cc.  The  correctness 
of  the  graduation  can  easily  be  tested  by  weighing  the  water  delivered  by 
it.  The  taps  are  at  first  left  open  to  air,  but  are  turned  after  a  few 
minutes  so  that  the  flasks  communicate  only  with  the  gauges  and  burette ; 
and  the  leveling  tubes  are  previously  adjusted  so  that  the  gauge  levels 


4I2  RESPIRATION 

are  at  the  zero  marks  and  the  burette  level  is  at  a  convenient  distance 
below  zero.  The  gauges  are  then  carefully  observed,  and  the  water  in 
the  bath  is  occasionally  stirred  by  blowing  air  through  it.  It  will  be 
found  that  when  both  the  gauges  are  exactly  adjusted  they  do  not  keep 
even  when  left  to  themselves  until  at  least  ten  minutes  after  the  blood 
flask  has  been  placed  in  the  bath.  The  alterations  are  compensated  by 
means  of  the  leveling  tubes;  and  when  the  gauges  have  come  steady, 
or  only  move  together,  the  burette  is  read  off  exactly.  The  confining 
liquid  is  distilled  water  containing  a  small  quantity  of  bile-salts  which 
make  the  readings  more  certain  and  sensitive. 

The  blood  flask  is  now  agitated  for  two  or  three  minutes  in  order 
that  the  blood  may  take  up  all  the  gas  it  is  capable  of  taking.  At  the 
same  time  it  is  laked  by  the  saponin.  In  the  process  of  agitation  the  flask 
is  never  removed  from  the  bath.  It  is  held  by  the  neck  with  forceps  or 
something  else  interposed  to  shield  it  from  the  warmth  of  the  fingers. 
The  gauges  are  now  again  adjusted,  and,  after  they  are  quite  steady, 
which  should  be  the  case  almost  at  once,  the  burette  is  again  read  off.  The 
difference  between  the  two  readings  gives  the  gas  absorbed  by  the  blood 
from  the  air.  From  this  we  can  calculate  the  volume  of  oxygen  absorbed 
by  the  haemoglobin. 

The  first  step  in  the  calculation  is  to  reduce  the  gas  absorbed  to  its 
dry  volume  at  o°  and  760  mm.  and  calculate  its  volume  per  100  cc.  of 
blood.  For  this  purpose  the  barometer  is  read  and  the  temperature  given 
by  a  thermometer  (not  shown  in  the  figure)  fixed  on  the  front  of  the 
stand,  with  the  bulb  close  to  the  upper  part  of  the  burette.  It  is  evident 
that  what  is  required  is  not  the  temperature  of  the  bath  or  connections, 
but  that  of  the  burette.  The  reduction  is  easily  made  with  the  help  of  a 
table  with  factors  for  correction,  such  as  that  at  page  60  (second  edi- 
tion) of  my  book  on  Methods  of  Air  Analysis. 

We  have  now  to  calculate  how  much  of  the  gas  absorbed  has  simply 
gone  into  physical  solution.  Blood  in  the  living  body  is  saturated  with 
nitrogen  at  the  partial  pressure  of  the  nitrogen  in  the  alveolar  air. 
Allowing  for  the  aqueous  vapor  present,  this  partial  pressure  is  about 
75  per  cent  of  the  existing  atmospheric  pressure.  The  coefficient  of  ab- 
sorption of  nitrogen  in  blood  at  38°C  is  .on,  according  to  Bohr's  de- 
termination. Hence  at  ordinary  atmospheric  pressure  there  will  be  .83  cc. 
of  nitrogen  (at  o°  and  760  mm.)  in  solution  in  100  cc.  of  blood.  The 
blood  in  the  flask  will  become  saturated  at  about  15°  with  nitrogen  at  a 
partial  pressure  of  about  78  per  cent  of  an  atmosphere ;  and,  as  the  co- 
efficient of  absorption  is  .016,  about  1.25  cc.  of  nitrogen  will  be  in 
solution  per  100  cc.  of  blood  saturated  with  air  at  15°.  Thus  100  cc.  of 
blood  will  take  up  .42  cc.  of  extra  nitrogen  on  saturation. 


RESPIRATION  413 

To  calculate  how  much  extra  oxygen  the  blood  will  take  up  in  simple 
solution,  we  must  know  the  partial  pressure  of  oxygen  at  which  the  blood 
taken  from  the  living  body  is  saturated,  and  this  can  be  deduced  pretty 
accurately  from  the  percentage  saturation  of  the  haemoglobin  and  the 
dissociation  curve  of  oxyhaemoglobin  in  human  blood.  Now  it  was  found 
by  Meakins  and  Davies13  that  the  haemoglobin  of  normal  human  arterial 
blood  is  about  95  per  cent  saturated,  which  corresponds  to  an  oxygen 
pressure  of  1 1  per  cent  of  an  atmosphere,  or  84  mm.  The  coefficient  of 
absorption  of  oxygen  in  blood  at  38°  is  .022.  Hence  there  will  be  .24  cc. 
of  oxygen  in  simple  solution  in  100  cc.  of  arterial  blood.  At  15°  the  co- 
efficient of  absorption  is  .031  and  at  ordinary  atmospheric  pressures  the 
partial  pressure  of  oxygen  in  the  bottle  will  be  20.5  per  cent  of  an 
atmosphere.  Hence  .63  cc.  of  oxygen  will  be  in  solution  in  100  cc.  of 
blood  saturated  with  air  at  15°,  and  the  extra  oxygen  taken  up  in  solu- 
tion will  be  .39  cc.  Thus  the  total  extra  gas  taken  up  in  solution  will  be 
.42  +  .39  =  .81  cc.  in  100  cc.  of  blood,  and  only  the  balance  of  the 
proportion  actually  taken  up  in  the  blood  flask  will  go  to  saturate  the 
haemoglobin.  Hence  if  the  temperature  of  the  water  bath  is  15°  the 
allowance  for  gas  in  simple  solution  will  be  .81  cc. 

If  the  bath  is  above  or  below  15°  this  allowance  will  be  a  little  less  or 
greater,  and  a  calculation  shows  that  for  each  degree  above  or  below  15°, 
between  the  temperatures  of  20°  and  10°,  the  allowance  will  have  to  be 
diminished  or  increased  by  .038  cc. 

An  example  will  make  the  calculation  of  the  percentage  saturation  of 
the  haemoglobin  clear.  Let  us  suppose  that  2.15  cc.  of  arterial  blood  have 
been  delivered  into  the  flask  and  the  constant  reading  of  the  burette 
after  temperature  equilibrium  had  been  obtained  was  .072  cc.,  and  after 
agitating  the  blood  .030.  Thus  0.042  cc.  of  gas  had  been  absorbed  from 
2.15  cc.  of  blood,  or  1.95  cc.  from  100  cc.  The  temperature  was  14°  and 
the  barometer  755  mm.  Hence  the  factor  for  reduction  to  dry  gas  at  o° 
and  760  mm.  was  0.930.  Therefore  the  dry  gas  at  standard  pressure  and 
temperature  was  1.81  cc.  The  temperature  of  the  bath  was  13°.  Hence 
.81  +  .08  =  .89  cc.  went  into  physical  solution,  so  that  0.92  cc.  of  oxygen 
was  absorbed  by  the  haemoglobin. 

To  determine  the  percentage  saturation  of  the  haemoglobin  it  is 
necessary  to  know  the  total  oxygen  capacity  of  the  haemoglobin ;  and  this 
can  now  be  determined  directly.  To  the  tube  passing  through  the  stopper 
of  the  blood  flask  there  is  attached  a  loop  of  wire  into  which  a  small 
tube  of  thin  glass  can  be  inserted.  In  the  tube  is  placed  .25  cc.  of  satu- 
rated ferricyanide  solution  and  the  flask  closed  and  reinserted  in  the 
water  bath  till  temperature  equilibrium  is  reached.  The  burette  is  again 

"Meakins  and  Davies,  Journ.  of  Patkol,  and  Bacter.,  XXIII,  p.  451,  1920. 


414  RESPIRATION 

read  off,  and  the  flask  turned  up  so  as  to  let  the  ferricyanide  flow  into 
the  blood  solution.  Before  doing  this,  however,  the  blood  solution  should 
be  observed  to  make  sure  that  it  is  perfectly  laked  and  transparent; 
otherwise  more  saponin  must  be  added.  The  flask  is  now  agitated  as 
long  as  gas  continues  to  come  off  as  shown  by  the  movements  of  the 
gauge.  This  will  take  three  or  four  minutes.  The  burette  is  again  read 
off,  which  gives  the  volume  of  oxygen  given  off.  This  is  reduced  to  dry 
volume  at  o°  and  760  mm.  and  per  100  cc.  of  blood. 

Let  us  suppose  that  the  oxygen  capacity  of  the  haemoglobin  in  the 
above  example  was  17.4  cc.  per  100  cc.  of  blood.  The  percentage  satura- 
tion of  the  haemoglobin  in  the  arterial  blood  was  therefore 

17.40 — .92 

100  x —  94.7. 

17.40 

It  is  easier  to  determine  the  oxygen  capacity  by  means  of  a  Gowers- 
Haldane  haemoglobinometer,  in  which  100  per  cent  corresponds 
to  an  oxygen  capacity  of  18.5.  For  this  purpose  a  sample  of  the 
blood  drawn  from  the  artery  is  used  for  the  determination.  In  the  above 
example  the  oxygen  capacity  of  17.4  corresponds  to  94  per  cent  on  the 
haemoglobinometer  scale,  and  the  range  of  error  in  carefully  made 
haemoglobinometer  determinations  is  only  about  0.5  per  cent.  The  ac- 
curacy of  both  methods  is  strikingly  shown  by  the  fact  that  in  36  determi- 
nations by  Meakins  and  Davies  of  the  oxygen  capacity  of  blood  from 
patients  and  healthy  persons  the  maximum  difference  between  the  re- 
sults by  the  haemoglobinometer  and  by  the  new  method  was  under  i  per 
cent  of  the  oxygen  capacity.14 

A  haemoglobinometer  can,  of  course,  be  exactly  standardized  by  the 
method  just  described.  If  the  haemoglobinometer  is  used,  it  is  unneces- 
sary to  use  saponin  or  ferricyanide  in  determining  the  percentage  satura- 
tion of  the  haemoglobin  in  the  sample  of  blood.  The  total  available 
oxygen  in  the  sample  of  arterial  blood  is  the  oxygen  combined  with 
haemoglobin  plus  the  dissolved  oxygen.  This  was,  in  the  above  example, 
16.48  +.24  =16.72  cc.  per  100  cc.  of  blood. 

If,  instead  of  being  normal  arterial  blood,  the  sample  was  venous 
blood,  or  arterial  blood  of  abnormally  low  saturation  with  oxygen,  the 
calculation  must  be  slightly  modified,  since  less  oxygen  in  simple  solu- 
tion is  present  in  the  sample.  Thus  if  the  blood  turned  out  to  be  only 
half  saturated  with  oxygen  the  partial  pressure  of  oxygen  in  the  sample 
would  only  be  about  4  per  cent  of  an  atmosphere.  Hence  there  would 
only  be  .09  cc.  of  dissolved  oxygen  present,  instead  of  .24  cc.  This  would 
increase  the  correction  at  15°  for  dissolved  gas  from  .81  to  .96  cc. — a 
difference  which,  however,  affects  the  result  but  little.  Ordinary  varia- 

14  Meakins  and  Davies,  Journ.  of  Pathol.  and,  Bacter.,  XXIII,  p.  454,  1920. 


RESPIRATION  415 

tions  of  barometric  pressure  do  not  sensibly  affect  the  correction,  but  at 
high  altitudes  the  correction  must  evidently  be  diminished  in  the  pro- 
portion of  about  o.i  cc.  for  every  100  mm.  of  diminution  in  atmospheric 
pressure. 

If  the  blood  is  taken,  not  from  the  living  body,  but  from  a  saturating 
vessel,  the  gases  dissolved  physically  must  be  calculated  on  the  same 
principle,  allowing  for  their  pressures  in  the  vessel.15 

The  method  just  described  has  been  tested  for  accuracy  in  several 
ways.  In  the  first  place  it  has  been  found  that  when  blood  fully  saturated 
with  air  at  room  temperature  is  placed  under  the  sodium  carbonate 
solution  in  the  ordinary  way  and  then  agitated  after  the  gauges  have 
become  steady,  there  is  no  sensible  variation  in  the  reading  of  the  burette 
afterwards.  The  constancy  of  the  reading  can  be  relied  on  to  .002  cc. 
with  careful  work.  Hence  the  percentage  saturation  can  be  relied  on  to 
0.5  per  cent,  or  the  oxygen  capacity  per  100  cc.  of  blood  to  o.i  cc.,  if  the 
measuring  pipettes  are  properly  calibrated.  This  is  as  good  a  result  as 
could  be  obtained  with  20  cc.  of  blood  by  means  of  the  original  ferri- 
cyanide  apparatus.  The  present  method  is  therefore  as  exact  as  the 
original  one  for  determining  the  oxygen  capacity  of  blood,  but  is  quicker 
and  more  convenient.  By  using  sodium  carbonate  instead  of  ammonia 
solution  the  errors  due  to  diminution  of  the  vapor  pressures  of  ammonia 
and  water  on  mixing  the  blood  with  the  solution  are  eliminated,  while 
the  use  of  saponin,  first  introduced  by  C.  G.  Douglas,  produces  the  laking 
of  the  blood  which  is  necessary  in  order  to  allow  the  ferricyanide  to 
act  on  the  oxyhaemoglobin.  The  fact  that,  as  has  been  found  by  Meakins 
and  Davies,  haemoglobinometer  estimations  coincide  within  i  per  cent 
with  the  results  by  this  method  furnishes  further  confirmatory  evidence. 

The  new  apparatus  gives  sharper  results  than  the  constant  volume 
method  which  Barcroft  and  I  described  in  1902.  This  is,  I  think,  partly 
due  to  the  larger  volume  (2  cc.)  of  blood  employed;  partly  to  the  fact 
that  the  disturbance  due  to  the  use  of  ammonia  solution  is  avoided  and  a 
sharper  index  of  temperature  equilibrium  is  given  by  the  two  gauges 
of  the  present  apparatus ;  and  partly  because  the  gauge  levels  are  always 
at  the  same  place,  whereas  in  the  constant-volume  apparatus  the  gauge 
levels  shift  to  places  wide  apart,  so  that  small  errors  due  to  varying 
capillarity  of  the  gauge  tubes  are  apt  to  tell.  It  is  thus  difficult,  with  the 
constant-volume  apparatus,  to  avoid  errors  within  2  per  cent  on  either 
side  of  the  actual  percentage  saturation. 

15  In  the  paper  by  Barcroft  and  myself  where  we  first  described  the  constant 
volume  blood-gas  apparatus,  the  correction  for  gas  in  simple  solution  was  un- 
fortunately given  incorrectly;  and  this  doubtless  accounts  for  the  somewhat 
distorted  forms  of  the  dissociation  curves  of  oxyhaemoglobin  in  Barcroft's  earlier 
experiments  on  this  subject. 


416  RESPIRATION 

When  it  is  desired  to  determine  the  CO2  content  of  the  blood  the 
procedure  must  be  modified,  as  sodium  carbonate  cannot  be  used,  and 
2  cc.  of  blood  would  give  too  much  CO2  for  the  capacity  of  the  burette, 
apart  from  other  causes  of  error.  Therefore  only  about  i  cc.  of  blood 
should  be  taken.  This  is  delivered  under  1.5  cc.  of  a  solution  of  4  parts 
of  ordinary  strong  ammonia  solution  (sp.  gr.  .88)  to  a  liter  of  boiled 
distilled  water,  and  a  trace  of  saponin  added.  To  avoid  the  presence  of 
any  carbonate  in  the  ammonia  the  strong  solution  is  first  shaken  up  with 
some  unslaked  lime  and  allowed  to  settle.  The  stock  of  dilute  solution 
is  kept  tightly  corked.  As  soon  as  the  ammonia  solution  is  placed  in  the 
flask,  the  latter  is  kept  tightly  corked  until  the  blood  is  added,  otherwise 
a  considerable  amount  of  CO2  may  diffuse  in  and  cause  error.  The  blood 
is  shaken  up  to  lake  it,  and  .25  cc.  of  ferricyanide  afterwards  added  to 
liberate  the  oxygen,  since  if  this  were  not  done  some  oxygen  might  be 
liberated  by  the  acid.  After  all  the  liberated  oxygen  has  been  shaken  off, 
the  small  glass  tube  containing  .25  cc.  of  20  per  cent  solution  of  tartaric 
acid  is  inserted  and  the  burette  read  off  after  the  gauges  are  steady.  The 
tartaric  acid  solution  is  then  spilt  into  the  blood  solution  and  the  flask 
agitated  under  water  till  the  CO2  has  completely  ceased  to  come  off,  as 
shown  by  the  gauge.  The  burette  is  then  adjusted  and  read  off  and  the 
volume  of  gas  given  off  reduced  to  its  dry  volume  at  o°  and  760  mm. 
and  calculated  per  100  cc.  of  blood.  Part  of  the  CO2  however,  remains 
dissolved  in  the  liquid  in  the  flask,  and  must  be  allowed  for.  This  liquid 
is  exactly  the  same  as  in  the  case  of  determination  of  CO2  by  means  of 
the  constant- volume  apparatus  described  by  Barcroft  and  myself,  so  the 
correction  is  made  in  a  similar  manner.  At  a  temperature  of  13°  the 
coefficient  of  absorption  of  CO2  in  this  liquid  was  found  to  be  i  .00.  Hence 
if  we  know  the  total  volume  of  the  flask  as  compared  with  the  volume 
of  gas  in  it  when  the  liquid  is  also  present,  and  the  temperature  of  the 
bath  is  13°,  the  total  CO2  liberated  from  the  blood  will  be  to  the  amount 
shown  by  the  burette  as  the  total  capacity  of  the  flask  to  the  volume  of 
gas  in  it  when  the  liquid  is  also  present.  The  capacity  of  the  flask  to  the 
cork  is  about  20  cc.  Let  us  suppose  that  as  determined  by  weighing  with 
the  cork  in  place  it  is  20.5  cc.,  including  the  capacity  of  a  piece  of  glass 
tubing  of  about  4  mm.  bore  and  two  inches  long  which  passes  through 
the  cork.  The  volume  of  liquid  in  the  flask  is  3.0  cc.  Hence  if  the  tempera- 
ture of  the  bath  is  13°  the  total  volume  of  CO2  liberated  is  obtained  by 

20  ^ 
multiplying  the  corrected  volume  actually  read  off  by  — —   or  adding 

17  per  cent.  If  the  temperature  is  above  or  below  13°  a  fortieth  must  be 
subtracted  from  or  added  to  this  addition,  since  the  solubility  of  CO2 
diminishes  by  about  a  fortieth  for  each  degree  above  13°,  and  increases 


RESPIRATION  417 

similarly  for  each  degree  below  13°.  The  glass  tubing  passing  through 
the  cork  is  4  mm.  in  bore  in  order  to  give  room  for  the  CO2  given  off 
without  its  coming  in  contact  appreciably  with  the  rubber  connecting 
tubing.  For  determining  CO2  in  blood  it  is  better  to  use  an  ordinary 
cork  than  a  rubber  stopper  in  the  blood  flask,  as  the  rubber  leads  to  a 
slow  absorption  of  CO2. 

A  further  negative  correction  is  required  for  any  CO2  present  in  the 
solutions  used,  or  absorbed  from  the  air  in  the  flask ;  also  for  the  small 
error  in  the  opposite  direction  owing  to  disappearance  of  ammonia 
vapor  from  the  air  of  the  flask.  The  joint  correction,  which  ought  to  be 
very  small,  and  may  be  either  positive  or  negative,  can  be  ascertained 
by  a  blank  experiment  in  which  boiled  distilled  water  in  place  of  blood 
is  used  in  the  flask.  Or  if  the  capacities  of  the  two  bottles  are  nearly 
equal  the  blank  experiment  may  be  performed  in  one  flask  along  with  the 
blood  experiment  in  the  other.  In  this  way  the  correction  is  eliminated. 

As  shown  by  this  method  by  Meakins  and  Davies,  arterial  blood  gives 
slightly  more  CO2  than  denbrinated  blood  at  the  same  partial  pressure 
of  CO2,  as  found  in  the  experiments  of  Christiansen,  Douglas,  and 
myself.16 

The  following  example  illustrates  the  mode  of  calculation.  The  volume 
of  CO2  given  off  from  i.oo  cc.  of  human  arterial  blood  was  0.482  cc.  as 
read  from  the  burette.  Reduced  to  dry  gas  at  o°  and  760,  and  calcu- 
lated per  100  cc.  of  blood,  this  was  45.9  cc.  The  correction  at  13°  for  the 
CO2  left  in  solution  was  16.5  per  cent,  but  as  the  temperature  of  the  bath 
was  15°  the  proper  correction  was  15.3  per  cent.  Hence  the  CO2  con- 
tained in  100  cc.  of  blood  was  52.9  cc.  A  blank  control  experiment  was 
made  simultaneously  in  the  other  flask,  so  there  was  no  further  correction. 

In  any  cases  where  both  the  oxygen  and  CO2  in  a  sample  of  blood  are 
required,  it  is  better  and  quicker  to  make  the  determinations  simul- 
taneously in  two  different  apparatus. 

For  the  proper  working  of  the  apparatus  it  is  essential  that  all  the 
joints,  including  the  cork,  should  be  absolutely  tight.  There  is  no 
difficulty  about  this  if  the  rubber  tubing  used  is  smooth  and  clean.  To 
test  for  tightness  the  burette  should  be  read  after  the  gauges  are  steady. 
Positive  or  negative  pressure  is  then  produced  for  some  time  in  the 
apparatus  by  raising  or  lowering  the  leveling  tubes.  On  readjusting  the 
gauges,  the  reading  should  be  exactly  the  same  as  before,  if  the  apparatus 
is  tight.  If  a  leak  exists  it  can  soon  be  localized  by  putting  pressure  on 
one  part  after  another  of  the  connections. 

The  apparatus  can  be  put  together  without  very  much  trouble,  and  if 

16  Christiansen,  Douglas,  and  Haldane,  Journ.  of  PAysiol.,  XLVIII,  p.  272, 
1914. 


4i8  RESPIRATION 

three-way  taps  are  not  available  T  tubes  may  be  substituted.  Messrs. 
Siebe  Gorman  &  Co.,  187  Westminster  Bridge  Road,  London  S.  E., 
supply  it. 

D.  Colorimetric  Determination  of  Percentage  Saturation  of 
Haemoglobin  with  CO 

This  very  convenient  method  is  used  in  determining  the  oxygen  pres- 
sure of  arterial  blood,  the  total  haemoglobin  in  the  body,  or  the  blood  vol- 
ume, as  well  as  for  investigations  as  to  the  properties  of  CO  haemoglobin 
and  the  phenomena  of  CO  poisoning.  It  depends  on  the  fact  that  a  dilute 
solution  of  CO  haemoglobin  has  a  pink  color,  quite  different  from  the 
yellow  color  of  similarly  diluted  oxyhaemoglobin. 

I  originally  used  this  color  difference  as  an  easy  and  delicate  means 
of  recognizing  the  presence  of  CO  in  blood  and  roughly  estimating  the 
saturation  with  CO;  and  I  then  thought  that  as  it  is  impossible  to 
recognize  by  the  difference  of  tint  a  difference  of  less  than  about  5  per 
cent  in  the  percentage  saturation  of  haemoglobin  with  CO,  the  method 
was  at  best  a  rough  one.  Various  recent  writers  have  fallen  into  the  same 
error.  Further  experience  showed  that  with  proper  precautions  the 
method  gives  results  of  great  accuracy.  The  following  description  is 
taken  almost  verbatim  from  the  account  of  the  method  given  in  1912  by 
Douglas  and  myself  in  our  paper  on  oxygen  secretion.17 

A  solution  of  normal  human  blood  (or  blood  from  the  animal  experi- 
mented on)  is  prepared  of  such  strength  as  to  correspond  to  about  0.5 
per  cent  of  the  proportion  of  haemoglobin  in  standard  human  blood  of 
100  per  cent  strength  by  the  Gowers-Haldane  haemoglobinometer  scale. 
Two  test  tubes  of  equal  bore  of  about  0.6  inch  are  selected,  and  into 
each  of  these  5  cc.  of  the  blood  solution  are  measured  with  a  pipette. 
From  a  o.i  per  cent  solution  of  carmine  in  ammoniacal  distilled  water 
(this  solution  being  kept  in  the  dark  in  a  cupboard)  a  dilute  solution  of 
carmine  in  distilled  water  with  a  strength  of  tint  about  equal  to  or  rather 
greater  than  that  of  the  blood  solution  is  then  prepared  in  a  measuring 
cylinder.  The  requisite  amount  of  dilution  (about  one-twentieth  of  the 
o.i  per  cent  solution  if  the  latter  has  been  recently  prepared)  can  easily 
be  estimated  by  the  eye,  and  can  be  obtained  at  once,  when  experiments 
are  made  daily,  by  diluting  to  a  definite  extent.  A  burette  is  filled  with 
the  carmine  solution,  and  another  burette  with  water.  The  blood  solution 
in  one  of  the  test  tubes  is  then  saturated  with  CO  by  allowing  coal  gas  to 
run  through  the  free  part  of  the  test  tube,  quickly  closing  the  tube  with 
the  thumb,  and  shaking  the  blood  solution  with  the  gas  for  a  few  seconds. 

"  Douglas  and  Haldane,  Journ.  of  PAysioL,  XLIV,  p.  305,  1912. 


RESPIRATION  419 

When  looked  at  against  the  sky,  the  solution  will  now  have  a  deep 
purplish-pink  tint,  as  compared  with  the  brownish  yellow  of  the  normal 
blood  solution.  The  carmine  is  now  added  from  the  burette  to  the  normal 
blood  solution  until  its  tint  is  about  equal  in  quality  to  that  of  the  satu- 
rated blood  solution.  It  will  then  probably  be  found  that  the  depth  of 
tint  is  too  great  in  the  tube  containing  the  carmine.  Water  is  then  added 
from  the  other  burette  until  the  depth  of  tint  is  equal,  and  if  necessary 
more  carmine,  until  complete  equality  of  both  tint  and  depth  of  color  is 
obtained.  In  judging  of  this,  the  test  tubes  should  be  held  up  against  the 
sky,  and  it  is  absolutely  necessary  to  change  them  repeatedly  from  side 
to  side ;  otherwise  gross  error  is  certain.  It  will  nearly  always  be  found 
that  the  right-hand  tube  appears  a  little  yellower  or  pinker  than  the  left- 
hand  one ;  and  a  little  deeper  or  less  deep  in  color.  This  difference  is  in 
reality  a  great  help  to  accuracy.  A  point  is  first  reached  when  the  tubes 
appear  equal  in  tint  or  depth  when  held  in  one  position,  but  unequal  in 
the  other,  and  the  end  point,  when  the  difference  is  the  same  on  one  side, 
whichever  tube  is  on  that  side,  can  be  estimated  with  great  delicacy. 
The  additions  of  carmine  (or  water)  are  continued  until  this  point  is 
passed ;  and  if  two  successive  additions  both  show  equality,  the  mean  of 
the  two  readings  is  taken  as  correct. 

To  the  carmine  solution  in  the  measuring  cylinder  a  proportion  of 
water  is  now  added  equal  to  what  had  to  be  added  from  the  water 
burette  to  the  carmine  required  to  reach  the  end  point  of  the  titration. 
The  carmine  solution  is  then  ready  for  use.  It  will  probably  be  found 
that  about  6  cc.  of  carmine  are  needed  to  reach  the  end  point.  The 
amount  required  varies,  however,  according  to  the  condition  of  the 
strong  carmine  solution  and  the  quality  of  the  daylight.  The  carmine 
solution  is  not  stable,  and  it  gradually  becomes  less  deep  in  color,  and 
redder  in  tint  than  when  first  prepared.  Hence  the  quantity  of  carmine 
solution  needed  increases  from  month  to  month,  and  the  extent  to  which 
it  has  to  be  diluted  for  use  diminishes.  If  the  dilute  solution  is  left  for  a 
day  or  two  exposed  to  light  it  becomes  very  markedly  redder  and  more 
dilute. 

The  titration  of  a  blood  sample  is  carried  out  as  follows.  One  or  two 
drops  of  blood  are  needed,  and  are  at  once  diluted  with  water.  Half  of 
the  dilute  solution  is  poured  into  one  of  the  two  test  tubes  (always  the 
same  one  as  that  used  for  the  saturated  blood  in  standardizing  the 
carmine),  and  5  cc.  of  the  normal  blood  solution  are  measured  with  a 
pipette  into  the  other.  Water  is  then  allowed  to  drip  from  a  tap  into  the 
solution  of  the  blood  under  examination  until  its  depth  of  tint  is  about 
equal  to  that  of  the  normal  solution.  Carmine  solution  is  now  added  to 
the  normal  blood  solution  from  the  burette  until  the  tints  are  equal, 


420  RESPIRATION 

more  water  being  also  added  to  the  other  tube  if  necessary.  The  solution 
under  examination  is  then  saturated  with  coal  gas  and  the  addition  to 
the  normal  blood  solution  of  carmine  is  continued  until  the  tints  are 
again  equal.  To  illustrate  the  method  of  calculating  the  result  we  may 
suppose  that  in  the  first  result  equality  of  tint  was  observed  with  1.2  and 
1.3  cc.  of  carmine,  mean  1.25,  and  that  in  the  second  6.4  and  6.8  cc.  gave 
equality,  mean  6.6;  the  percentage  saturation  X  is  then  given  by  the 
result  of  the  following  proportion  sum : 

6.6  1.25 

— r— r-: ; :  :  100 :  X 

5  +  6.6      5  +  1.25 

or,  more  simply, 

6.25       6.6 

100  x  x =  35.1  per  cent. 

1.25       n.6 

It  is  clear  that  the  more  carmine  has  already  been  added  to  the 
normal  blood  solution  the  less  effect  on  its  tint  will  any  further  addition 
have.  Hence  in  approaching  the  point  of  equality  only  o.i  cc.  is  added  at 
a  time  if  not  more  than  2  cc.  have  already  been  added,  whereas  after 
already  adding  6  cc.  it  is  useless  to  add  less  than  about  0.4  cc.  at  a  time. 

The  titration  is  repeated  with  the  other  half  of  the  blood  solution 
for  further  safety,  and  it  will  be  found  that  apart  from  accidents  the 
two  results  will  nearly  always  agree  within  i  per  cent  of  the  total  satu- 
ration. This  accuracy  is  very  surprising  at  first  sight,  since  colorimetric 
determinations  have  in  general  a  rather  bad  reputation  among  chemists. 
The  carmine  titration  is  also  no  ordinary  colorimetric  titration,  but  one 
in  which  the  quality,  and  not  the  density,  of  tint  is  estimated.  We  believe 
that  the  bad  results  commonly  obtained  with  "colorimeters"  are  due  to 
the  two  solutions  being  in  some  fixed  position  determined  by  the  apparatus 
used.  An  error  of  10  per  cent  or  more  may  easily  occur  from  this  cause. 
Far  more  accurate  results  can  be  obtained  with  two  ordinary  test  tubes 
repeatedly  transposed,  as  above  described,  than  with  complicated  and 
expensive  colorimeters. 

It  will  be  found  that  the  amount  of  carmine  giving  equality  varies  dis- 
tinctly for  different  individuals.  The  proportional  difference  is,  however, 
the  same  at  the  two  stages  of  the  titration,  so  that  the  percentage  result 
obtained  is  the  same.  For  the  same  individual  the  amount  of  carmine 
needed  varies,  also,  with  different  qualities  of  daylight,  and  is  usually 
less  towards  evening.  This  does  not  affect  the  percentage  result,  however, 
provided  that  the  two  stages  of  the  titration  are  completed  by  the  same 
light. 

All  these  differences  are  due  to  the  facts  that  the  two  solutions  are 
not  spectrally  identical;  nor  is  the  daylight  at  different  times  of  day; 
nor  are  the  retinae  of  different  persons  equally  sensitive  to  differences 


RESPIRATION  421 

in  any  particular  part  of  the  spectrum;  nor,  finally,  is  any  part  of  the 
retina  of  one  individual  constant  in  its  excitability  for  either  white 
light  or  colored  light;  the  excitability  of  any  one  part  being  dependent 
on  side  light  falling  on  neighboring  parts  of  the  retina.  The  numerous 
colorimeters,  haemoglobinometers,  etc.,  in  which  these  sources  of  error 
cannot  be  eliminated,  are  liable  to  very  gross  error,  and  appear  to  be 
responsible  for  the  discredit  under  which  colorimetric  methods  suffer. 

With  ordinary  artificial  light  the  differences  in  tint  between  the  various 
solutions  become  almost  invisible.  The  dimmest  daylight  is  better  than 
ordinary  artificial  light.  With  blue  spectacles,  however,  the  differences 
become  very  evident,  and  fairly  good  results  can  be  obtained  in  the 
titration  if  the  carmine  is  made  of  the  proper  strength  (very  much 
stronger)  to  suit  the  light.  Daylight  is,  however,  far  better. 

It  is  essential  to  accuracy  with  the  carmine  method  that  the  carmine 
solution  should  accurately  match  the  standard  blood  solution  in  depth  of 
color.  If  the  two  do  not  correspond,  it  is  easy  enough  to  get  a  result: 
for  when  the  solution  in  one  test  tube  is  too  deep  in  color  it  is  only 
necessary  to  incline  the  other  in  order  to  make  its  depth  of  tint  appear 
equal.  The  calculation  of  the  percentage  saturation  becomes  fallacious, 
however,  as  is  easily  seen.  One  source  of  slight  error  in  the  titrations  is 
that  a  carmine  solution  which,  when  made  up,  exactly  matches  the  blood 
solution  in  depth,  may,  towards  evening,  be  rather  too  strong,  owing  to 
change  in  the  light.  This  change  can,  however,  be  detected  and  rectified 
very  quickly,  and  attention  would  automatically  be  called  to  it  by  the 
fact  that  considerably  less  carmine  than  before  would  suffice  to  produce 
the  tint  of  fully  saturated  blood  solution. 

A  further  source  of  possible  fallacy  depends  on  the  liability  of  blood 
solution  to  decomposition.  It  is  essential  that  the  blood  should  be  fresh, 
and  diluted  with  clean  water  in  a  perfectly  clean  vessel.  Solution  which 
has  been  kept  more  than  a  few  hours  is  useless.  It  may  show  no  methae- 
moglobin  band,  and  appear  to  be  unaltered;  but  on  saturating  it  with 
CO  it  will  probably  no  longer  give  the  full  pink  color  of  undecomposed 
haemoglobin,  and  its  depth  of  color  will  also  be  found  to  be  less  than 
before.  It  is  thus  mixed  with  colored  decomposition  products  which  make 
it  useless  for  titration.  The  tint  on  saturation  with  CO  affords  a  far  more 
delicate  index  than  spectroscopic  examination  of  the  freedom  of  a  blood 
solution  from  pigments  other  than  haemoglobin. 

When  blood  saturated,  or  partly  saturated,  with  CO  is  diluted  with 
water,  a  small  part  of  the  CO  must  necessarily  go  into  solution  in  the 
water,  as  some  dissociation  of  the  CO-haemoglobin  occurs.  To  demon- 
strate this  it  is  only  necessary  to  saturate  some  blood  with  coal  gas  and 
dilute  some  of  it  to  0.5  per  cent  with  water.  It  will  be  seen  at  once  that 


422  RESPIRATION 

the  diluted  blood  is  distinctly  less  pink  than  some  of  the  same  solution  re- 
saturated  with  coal  gas ;  and  on  titration  the  blood  which  has  been  simply 
diluted  will  be  found  to  be  not  more  than  88  or  89  per  cent  saturated. 
The  percentage  dissociation  can  be  calculated  if  we  know  the  partial 
pressure  of  CO  corresponding  to  various  percentage  saturations  of  the 
haemoglobin  at  room  temperature,  and  also  the  coefficient  of  solubility 
of  CO. 

In  the  case  of  human  blood,  half-saturation  occurs  at  room  tempera- 
ture in  presence  of  air  with  about  .05  per  cent  of  CO.  Hence  with  50  per 
cent  saturation  of  a  blood  solution  saturated  with  air  the  partial  pressure 
of  CO  will  be  .05  per  cent  of  an  atmosphere.  Now  100  cc.  of  water  (and 
presumably  also  of  a  very  dilute  blood  solution)  dissolves  about  2.5  cc. 
of  CO  from  an  atmosphere  of  pure  CO  at  room  temperature  (i5°C.),  so 
that  at  a  partial  pressure  of  .05  per  cent  it  will  dissolve  2.5  x  .0005  — 
.00125  cc.  of  CO,  whereas  100  cc.  of  0.5  per  cent  blood  solution  can  take 
up  in  chemical  combination  .0925  cc.  of  CO.  Hence  the  proportion  of  the 
haemoglobin  dissociated  is  .00125  in  .0925,  or  1.35  per  cent,  so  that  if 
50  per  cent  saturation  were  found  by  titration  to  be  present  we  should 
require  to  add  1.35  per  cent  to  obtain  the  true  result.  By  a  similar 
calculation  we  find  that  if  the  blood  were  found  by  titration  to  be  89 
per  cent  saturated,  we  should  have  to  add  on  u  per  cent  in  order  to 
obtain  the  true  result,  which  would  thus  be  100  per  cent.  When  human 
blood  is  fully  saturated  with  coal  gas,  the  result  actually  found  by  titra- 
tion, after  dilution  of  the  blood  to  0.5  per  cent,  is  89  per  cent,  provided 
the  light  is  not  bright.  Hence  the  calculation  agrees  with  the  actual  result. 
In  the  brighter  light  of  the  middle  of  the  day  the  result  is,  however,  2  or 
3  per  cent  lower,  even  with  a  north  light ;  and  on  going  outside  so  as  to 
increase  the  light,  and  avoid  the  absorption  of  actinic  rays  by  window 
glass,  the  result  is  still  lower.  This  effect  is  due,  as  was  pointed  out  by 
Haldane  and  Lorrain  Smith,  to  the  action  of  actinic  rays  in  dissociating 
CO  haemoglobin.  The  varying  effect  of  light  renders  the  carmine  titration 
with  very  high  saturations  of  the  blood  with  CO  somewhat  uncertain. 
With  low  saturations,  such  as  we  have  usually  worked  with,  any  error  due 
to  this  cause  is  trifling.  We  have  at  all  times  avoided  bright  light  as  far 
as  possible,  and  where  it  was  necessary,  as  in  the  case  of  dissociation 
curves,  to  titrate  with  high  saturations  of  the  blood,  up  to  80  or  even 
85  per  cent,  we  have  done  the  titrations  by  evening  light.  As  an  alterna- 
tive, we  might  have  used  narrower  test  tubes  and  a  greater  concentration 
of  the  blood  solution,  so  as  to  diminish  the  correction  for  dissociation; 
but  it  is  easier  to  judge  the  tints  accurately  when  ordinary  test  tubes  are 
employed,  and  comparatively  few  determinations  were  needed  with  very 
high  saturations. 


RESPIRATION 

The  following  scale  of  corrections  was  used  for  human  blood. 


423 


Observed  -percentage 

Correction 

saturation 

added 

10  percent 

0.15 

20          " 

0-35 

30 

0.6 

40 

0.9 

50 

1-35 

60       " 

2.0 

70       " 

3-i 

80       " 

5-4 

89 

II.O 

For  mouse  blood  the  corrections  used  were  50  per  cent  higher,  since 
the  partial  pressure  of  CO  required  to  produce  a  given  saturation  of  the 
blood  with  CO  is  about  50  per  cent  higher  for  mice  than  for  men. 

As  already  mentioned,  the  results  of  duplicate  or  triplicate  titrations 
of  the  same  sample  of  blood  agree  very  closely,  the  variation  in  the  per- 
centage saturation  found  hardly  exceeding  i  per  cent  or  0.5  per  cent 
from  the  mean.  When,  as  in  determinations  of  arterial  oxygen  pressure, 
two  samples  not  differing  much  in  percentage  saturation  are  compared 
successively  with  the  same  standard  blood  solution,  the  difference  in  their 
percentage  saturations  with  CO  can  be  determined  with  corresponding 
accuracy;  for  any  errors  due  to  imperfect  preparation  of  the  standard 
solutions,  or  to  the  allowance  for  dissociation,  will  affect  both  results 
equally.  To  determine  the  absolute  range  of  the  latter  errors  we  made  a 
number  of  analyses  of  definite  mixtures  of  normal  blood  with  the  same 
blood  saturated  with  coal  gas.  The  coal  gas  contained  about  7  per  cent 
of  CO,  and  allowance  was  made  for  the  small  amount  of  CO  present  in 
simple  solution  in  the  saturated  blood. 

The  ox  blood  used  for  these  mixtures  was  measured  out  from  a  pipette, 
the  blood  being  kept  constantly  stirred  to  prevent  sedimentation  of  the 
corpuscles.  This  method,  though  fairly  accurate,  is  liable  to  slight 
errors  on  account  of  variations  in  the  quantity  of  blood  which  is  left 
adhering  to  the  pipette.  The  following  percentage  saturations  were  ob- 
tained on  different  occasions.  The  same  carmine  solution  was  used  by 
both  observers. 

In  series  (2)  and  (3)  the  mixtures  were  made  with  blood  laked  by 
dilution  to  half,  and  were  unknown  to  the  observer.  In  (i)  and  (4)  the 
mixtures  were  made  with  whole  blood,  and  were  known  to  one  observer. 
In  (4)  each  observer  made  up  his  own  carmine  solution. 


424 


RESPIRATION 


It  will  be  seen  that  the  maximum  error  was  2.0  per  cent,  this  including 
any  error  in  making  the  blood  mixtures  and  standardizing  the  carmine 
solutions.  With  double  determinations  the  error  was  considerably  less. 


Found. 

(i)    Calculated, 

Found                   (3)    Calculated          (C 

.£.£>.) 

33-7 

(33-9   (J.S.H.) 

20.3 

20.9 

(34.0  (C.G.D.) 

33-9 

32.1 

50.8 

49.2 

(76.0  (J.  S.  H.) 

67.7 

68.1 

75-8 

(76.8  (C.G.D.) 

(75.2   (J.S.H.) 

(4) 

Found 

(2)    Calculated, 

Found  (/.  S.  H.*)        Calculated 

(C.G.D.-)     (J. 

S.H.) 

25.4 

26.8                          1  1.2 

10.3 

11.4 

33-9 

338                          25.2 

26.0 

27.1 

50.8 

52.3                          50.5 

5L9 

52.5 

677 

68.3                          80.8 

79-9 

81.4 

E.  Determination  of  Blood  Volume  in  Man  during  Life  by  CO 

Since  CO  is  not  oxidized  or  otherwise  destroyed  in  the  living  body, 
and  since  it  forms  a  relatively  very  stable  molecular  compound  with 
haemoglobin,  but  with  no  other  substance  in  the  body,  it  is  evident  that 
if  we  administer  to  an  animal  a  known  amount  of  CO,  and  then  de- 
termine the  percentage  saturation  of  the  haemoglobin  with  CO  and  the 
total  CO  capacity  of  a  given  volume  of  blood,  we  can  determine  the  CO 
capacity  of  the  total  blood  in  the  body,  and  hence  deduce  also  the  blood 
volume.  The  blood  volume  during  life  was  first  determined  in  this  way 
by  Grehant  and  Quinquaud,18  who  used  dogs  for  the  purpose  and  em- 
ployed the  blood  pump  for  the  blood-gas  analyses.  In  1900  Lorrain 
Smith  and  I  introduced  a  much  simpler  method,  easily  applicable  to 
man;19  and  this  method  has  been  extensively  used  for  physiological, 
clinical,  and  pathological  work,  as  mentioned  in  Chapter  X. 

The  apparatus  required  for  administering  the  CO  to  a  man  is  shown 
diagramatically  in  Figure  104.  The  subject  breathes  through  a  glass 
mouthpiece  A,  the  nose  being  clipped  or  held.  The  mouthpiece  communi- 
cates by  ^-inch  rubber  tubing  with  a  bladder  or  india-rubber  bag  B  of 

18  Grehant  and  Quinquaud,  Journ.  de  I'anat.  et  de  la  -physwl.,  p.  564,  1882. 
M  Haldane  and  Lorrain  Smith,  Journ.  of  Physwl.,  XXV,  p.  331,  1900. 


RESPIRATION 


425 


at  least  2  liters  capacity.  Between  the  bag  and  mouthpiece  there  is  inter- 
posed a  cylindrical  metal  vessel  containing  moist  granulated  soda  lime 
or  other  suitable  absorbent  to  absorb  CO2.  The  end  of  this  vessel  may  be 
made  to  screw  on  and  off,  with  an  air-tight  rubber  washer;  or  may  be 
made  in  two  pieces,  the  outer  of  which  slides  over  the  inner,  as  shown 
in  the  figure,  the  junction  being  made  air  tight  with  plasticine.  The  soda 


Figure  104. 
Apparatus  for  determining  blood  volume  in  man. 

lime  is  kept  in  position  by  two  circular  pieces  of  wire  gauze,  one  of  which 
is  pushed  into  the  end  of  the  inner  vessel,  and  the  other  into  the  end  of 
the  outer  vessel.  Good  soda  lime  can  be  made  by  stirring  fresh  slaked 
lime  in  powder  with  a  strong  solution  of  caustic  soda  till  the  mixture 
granulates,  and  then  sifting  off  the  fine  powder  and  coarse  lumps  by 
means  of  two  sieves.  Granulated  caustic  soda  will  also  answer.  There 
should  be  no  appreciable  resistance  to  breathing,  and  one  tin  of  soda 
lime  should  last  for  several  experiments.  When  the  soda  lime  is  spent  it 
ceases  to  heat,  and  the  breathing  begins  to  become  increased,  owing  to 
unabsorbed  CO2. 

The  narrow  graduated  cylinder  D  is  filled  under  water  with  CO,  of 
which  a  stock,  prepared  from  formic  and  pure  sulphuric  acids,  can  be 
kept  in  a  large  bottle.  Just  before  the  experiment,  some  of  the  CO  is,  by 
turning  the  water  tap  E,  driven  out  through  the  test  tube  and  3-way  tap 
F  to  the  outside.  In  this  way  all  the  air  is  expelled  up  to  the  3-way  tap. 
The  water  tap  is  then  closed,  and  afterwards  the  3-way  tap.  Oxygen  from 
a  steel  cylinder  is  now  turned  on  through  the  tube  C  to  displace  CO 


426  RESPIRATION 

from  the  tubing,  which  is  then  connected  with  the  bag  as  shown  in  the 
figure,  and  the  bag  filled  pretty  full  with  oxygen.  Meanwhile  the  height 
of  the  water  in  the  cylinder  is  accurately  read  off,  and  the  temperature 
of  the  cylinder  and  barometric  pressure  noted. 

The  subject  of  the  experiment  now  begins  to  breathe  from  the  bag, 
oxygen  being  supplied  as  required.  The  water  tap  is  now  slightly 
opened,  and  the  tap  F  turned  so  as  to  let  CO  as  well  as  oxygen  pass.  The 
required  volume  of  CO  is  in  this  way  very  gradually  driven  in  from  the 
measuring  cylinder,  about  20  cc.  being  passed  in  per  minute.  After  the 
CO  has  been  passed  in,  the  water  tap  is  turned  off,  and  the  3-way  tap 
turned  so  as  to  shut  off  the  CO.  The  CO  is  absorbed  from  the  bag  very 
rapidly  and  completely.  The  oxygen  supply  is  continued  for  at  least  ten 
minutes,  after  which  the  subject  is  allowed  to  absorb  most  of  the  oxygen 
in  the  bag.  About  1 5  minutes  after  the  last  of  the  CO  has  been  given,  a 
drop  or  two  of  blood  is  taken  and  diluted  for  analysis  by  the  carmine 
method  described  above.  At  the  same  time  the  oxygen  capacity  of  the 
blood  is  determined  in  the  ordinary  way  by  the  Gowers-Haldane  haemo- 
globinometer.  For  further  certainty  it  is  well  to  make  both  determina- 
tions in  duplicate. 

As  a  little  air  always  gets  mixed  with  the  CO,  a  sample  of  the  CO  in 
the  cylinder  should  be  taken  for  analysis.  It  is  usually  sufficient  to 
determine  the  CO2  (of  which  none  should  be  present)  and  oxygen.  From 
the  latter  the  proportion  of  air  can  be  deduced. 

Let  us  suppose  that  150  cc.  of  CO  were  given,  the  temperature  12°, 
and  the  barometer  765  mm. ;  also  that  there  was  0.82  per  cent  of  oxygen 
in  the  CO,  corresponding  to  3.9  per  cent  of  air.  150  cc.  of  gas  saturated 
with  moisture  would  correspond  to  142.5  cc.  of  dry  gas  at  o°  and  760  mm. 
But  as  3.9  per  cent  of  this  was  air,  only  137  cc.  of  CO  were  administered. 
Let  us  also  suppose  that  the  percentage  oxygen  capacity  of  the  subject's 
blood  was  18.1  (98  per  cent  by  the  haemoglobinometer),  and  the  per- 
centage saturation  with  CO  was  19.5.  The  total  oxygen  capacity  or  CO 

capacity  must  have  been  137  x =703  cc. ;  the  blood  volume  703  x 

i9-5 

IOO 

=3880  cc.  If  the  subject's  weight  was  60  kilos  this  corresponds  to 

18.1 

6.5  liters  of  blood  to  100  kilos  of  body  weight;  and  this  result  is  usually 
expressed  as  a  blood  volume  of  6.5  per  cent  of  the  body  weight. 

In  the  original  description  of  our  method,  we  directed  that  the  blood 
sample  should  be  taken  within  two  or  three  minutes  of  the  cessation  of 
administration  of  CO,  as  we  assumed  that  by  that  time  the  CO  would 
be  evenly  distributed  in  the  blood  all  over  the  body.  The  results  from 
samples  taken  three  minutes  after  the  first  sample  confirmed  this  as- 


RESPIRATION  427 

sumption.  When,  however,  Douglas  and  Boycott  made  a  number  of  de- 
terminations with  a  much  larger  bag  which  necessitated  continuation  of 
the  breathing  for  a  considerable  time  after  the  CO  had  been  given,  they 
obtained  higher  average  results  for  the  blood  volume  in  man  than 
Lorrain  Smith  and  I  had  got.  Douglas  and  I  therefore  reinvestigated  the 
question  as  to  how  long  the  CO  requires  to  distribute  itself  equally,  and 
found  that  when  the  samples  were  taken  only  two  or  three  minutes  after 
cessation  of  the  administration  of  CO  the  percentage  saturations  of  the 
blood  were  from  10  to  25  per  cent  higher  than  15  minutes  later.  After 
10  to  15  minutes,  however,  the  saturation  remained  constant  if  the 
subject  continued  to  breathe  from  the  bag.  Our  original  experiments  gave, 
therefore,  results  for  the  blood  volume  which  were  too  low — probably  by 
about  25  per  cent.  The  average  blood  volume  in  man  by  the  CO  method 
is  about  6.5  to  7  per  cent  of  the  body  weight,  and  the  total  oxygen  capacity 
of  the  haemoglobin  about  i.i  to  1.3  liters  per  100  kilos  of  body  weight. 

It  is  probable  that,  as  regards  most  of  the  circulating  blood,  mixture 
with  any  added  substance  such  as  CO  takes  place  very  rapidly.  In  some 
parts  of  the  body,  however,  the  circulation  is  so  slow  that  a  considerable 
time  is  required  for  mixture. 

Douglas,20  and  also  Boycott  and  Douglas21  applied  the  above  de- 
scribed CO  method  to  animals,  and  took  the  opportunity  of  comparing  the 
results  with  those  obtained  by  the  older  colorimetric  method  of  Welcker, 
which  can  only  be  applied  after  death.  The  series  by  Douglas  showed  an 
average  difference  of  — 3  per  cent,  and  that  of  Boycott  and  Douglas  of 
+5-5  per  cent  with  the  CO  method  as  compared  with  the  Welcker  method. 
It  is  evident,  therefore,  that  no  substance  except  haemoglobin  combines 
with  CO.  It  must  be  remembered,  however,  that  many  of  the  muscles 
contain  some  haemoglobin,  and  that  by  both  methods  this  small  fraction 
of  the  total  haemoglobin  is  estimated  as  if  it  belonged  to  the  blood. 

In  using  the  CO  method  for  human  experiments  it  is  necessary  to 
adjust  the  volume  of  CO  administered  to  the  patient's  weight  and  prob- 
able oxygen  capacity,  so  that  the  percentage  saturation  of  his  haemo- 
globin is  not  likely  to  rise  above  about  20;  otherwise  slight  headache 
may  result.  For  persons  of  ordinary  weight  about  1 50  cc.  of  CO  would 
be  suitable ;  but  in  cases  of  pernicious  anaemia  or  anaemia  from  loss  of 
blood,  and  in  children  or  persons  of  low  weight,  far  less  CO  should  be 
given.  On  the  other  hand  in  cases  of  polycythaema  it  may  be  necessary 
to  give  300  cc.  or  more  in  order  to  obtain  a  percentage  saturation  suffi- 
cient for  a  satisfactory  titration  of  the  blood.  As  CO  only  leaves  the 
blood  slowly  when  the  percentage  saturation  is  low,  it  is  hardly  neces- 
sary, except  in  very  exact  experiments,  to  keep  the  patient  breathing 
from  the  bag  after  all  the  CO  has  been  absorbed. 

20  C.  G.  Douglas,  Journ.  Physiol.,  XXXIII,  p.  493,  1906,  and  XL,  p.  472,  1910. 
n  A.  E.  Boycott  and  C.  G.  Douglas,  Journ.  Path,  and  Bact.,  XIII,  p.  256,  1909, 
and  A.  E.  Boycott,  same  Journal,  XVI,  p.  485,  1911. 


THE  UNIVERSITY  LIBRARY 

UNIVERSITY  OF  CALIFORNIA,  SANTA  CRUZ 

SCIENCE  LIBRARY 

This  book  is  due  on  the  last  DATE  stamped  below. 


REC'D  DEC  1  5 
N.B.-HOLD 

JUN9    1971 
REC'D  JUN  1  7 
AUG  30  1972 


APR  2?  1976 

Rtli'U  APR  2  8 
MAY  I  3 

^ 


50m-4,'69(J7948s8)2477 


AUG  2     1978 
AUG     i  1978 

7 


REC'D  SEP  1  1  1978 
NOV5    1978 

REC'D  OCT  2  5  1978 
MAY  2     1980 

MAY  2  5  1980 
REC'D  JUN  3     1980 

JED  FEB1?  1981 

)EC  14*99 

DEC  05  1993 


QP121.H26  Sci 


3  2106  00259  4924 


